|Year : 2015 | Volume
| Issue : 3 | Page : 93-105
Neural cell adhesion molecule (cluster of differentiation 56) in health and disease
Syed Z. A Zaidi1, Ibraheem H Motabi1, Ali Al-Shanqeeti2
1 Department of Adult Hematology/BMT, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia
2 National Blood and Cancer Center, King Abdullah Road, Riyadh, Saudi Arabia
|Date of Web Publication||18-Sep-2015|
Syed Z. A Zaidi
Department of Adult Hematology/BMT, Comprehensive Cancer Center, King Fahad Medical City, P. O. Box: 59046, Riyadh 11525
Source of Support: Nil., Conflict of Interest: There are no conflicts of interest.
Cluster of differentiation (CD) 56, a member of the immunoglobulin superfamily, and an isoform of neural cell adhesion molecule (NCAM), was the first cell adhesion molecule to be identified. NCAM (CD56) plays an important role both in human health and in disease. Human NCAM gene is located on chromosome 11q23. CD56 antigen is a 175–185-kD cell surface glycoprotein expressed on all subsets of human natural killer (NK) cells except a small minority of CD56− NK-cell, on subsets of CD4+/CD8+ T-cells, interleukin-2-activated thymocytes, bone marrow macrophages, osteoclasts, and on adrenal gland and neural tissues. NCAM is important in calcium independent cell-cell interactions that mediate homotypic and heterotypic cell-cell and cell-matrix adhesions. At least 27 alternatively spliced NCAM mRNAs are produced giving a wide diversity to NCAM isoforms sharing a similar structural organization. NCAM in the cerebellum and cerebral cortex mediates homophilic adhesion of neural cells, and plays an important role in brain development, emotions, and memory functions. While CD56+ NK-cells play an important role in defense against infections, tumor remission, normal pregnancy and graft rejection. Malignancies expressing CD56 are usually aggressive, with more potential for metastasis and extramedullary/central nervous system involvement, and may respond to new CD56-linked targeted therapies.
Keywords: Cluster of differentiation 56, infection, malignancies, natural killer-cells, neural cell adhesion molecule
|How to cite this article:|
Zaidi SZ, Motabi IH, Al-Shanqeeti A. Neural cell adhesion molecule (cluster of differentiation 56) in health and disease. J Appl Hematol 2015;6:93-105
|How to cite this URL:|
Zaidi SZ, Motabi IH, Al-Shanqeeti A. Neural cell adhesion molecule (cluster of differentiation 56) in health and disease. J Appl Hematol [serial online] 2015 [cited 2018 May 23];6:93-105. Available from: http://www.jahjournal.org/text.asp?2015/6/3/93/165655
| Introduction|| |
Cluster of differentiation (CD) 56, a member of the immunoglobulin (Ig) superfamily, and an isoform of neural cell adhesion molecule (NCAM), is thefirst cell adhesion molecule to have been identified. At least 27 alternatively spliced NCAM mRNAs produce several isoforms. Human NCAM gene is located on chromosome 11q23. The CD56 antigen, recognized by the monoclonal antibodies anti-Leu-19 and NKH-1 in tissues, is a 175–185-kD type-1 cell surface glycoprotein [Figure 1]., CD56 contains a 689 amino acid extracellular domain which contains 5 Ig-like C2-type domains, 2 fibronectin type-3 domains and 6 potential N-glycosylation sites [partially depicted in [Figure 1]. CD56 is expressed on all subsets of human natural killer (NKs) cells except a small minority of CD56− NKs, CD4+ and CD8+ subsets, interleukin-2 (IL-2)-activated thymocytes, blood monocyte subset, bone marrow macrophages, osteoclasts, adrenals, and neural tissues (neurons and glia).,
|Figure 1: Neural cell adhesion molecule/CD56 ribbon structure and immunohistochemical expression in natural killer/T-cell lymphoma. (a) Neural cell adhesion molecule IgI-IgII quaternary ribbon structure and homophilic binding shown using the A-B dimer. Two IgI-IgII molecules form a cross shaped homodimer. Molecule A is shown in blue and molecule B in magenta with their individual domains labeled IgI and IgII. (b) Immunohistochemistry revealing strong cluster of differentiation expression in a nasal-type natural killer/T-cell lymphoma (×400)|
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NCAM is important for calcium independent cell-cell interactions that mediate cell-cell and cell-matrix adhesions. CD56 has a clear function in homotypic binding to CD56 molecules on other cells. CD56 in the cerebellum and cerebral cortex (on neurons, astrocytes, and Schwann cells) predominantly mediates hemophilic adhesion of neural cells. CD56+ NKs are important in defense against viral infections, tumor remission, and graft rejection.
Malignancies expressing CD56 are usually aggressive, with more potential for metastasis and extramedullary/central nervous system (CNS) involvement, and may respond to new CD56-linked targeted therapies. This aspect will be reviewed later elsewhere due to space limitations.
| Cd56 in Normal Development|| |
Neuronal Development and Intercellular Communication
During development, CD56 is abundantly expressed in the fetal nervous system, involving its adhesion mechanisms, formation of the neural circuit, and development of the muscles., IgCAMs are involved in brain development, and in maintenance and function of the neural network in adults. Additionally, heterophilic adhesion by CD56 occurs between neuronal cells and chondroitin sulfate proteoglycans of cell matrix. NCAM maintains groups of cells at key sites during early development and in adulthood.
The binding of NCAM to cells leads to signaling events, some of which result in changes in gene expression. NCAMs induce neurite outgrowth through fibroblast growth factor receptor (FGFR) and acts on p59Fyn signaling pathway. The developmental events (including cell migration, proliferation, and differentiation) can result both from their adhesive and signaling properties.
The hypothesized combined factors that control the expression of CAMs during early neural development include the coordinate expression of homeobox and paired box (Hox and Pax) proteins in the neural axis leading to the differential expression of particular CAM genes.
Functional assays of Schwann cell migration and axon growth of CNS neurons suggest physiological significance for the glial cell line-derived neurotrophic factor and its receptor NCAM.,
CD56 in Emotions and Learning-Role of Fibroblast Growth Factor Loop Peptide
A plethora of work suggests that NCAM is required in the adult brain for different behavioral functions. Posttranslational attachment of polysialic acid (PSA) to NCAM (PSA-NCAM) provides an additional mechanism for synaptic control. NCAM180, an isoform enriched at postsynaptic sites in CNS, may have prominent role in synaptic stability and memory formation., NCAM and PSA-NCAM regulate emotion, learning, memory processes, including the modulation of learning induced by emotional aspects. Plappert et al. experiments on null mutant (NCAM −/−) mice and their wild type littermates (NCAM +/+) mice suggest NCAM role in the relevant brain areas, like amygdala and/or the hippocampus. A 15-amino acid peptide, mimicking second FnIII module of NCAM, termed the fibroblast growth loop (FGL) peptide, binds to and activate FGFR1 and stimulates neurite outgrowth. FGL strongly enhances spatial memory, spatial learning, and emotional learning. The evidence supports the use of NCAM-related compounds, like FGL peptide, for the treatment of devastating neurological disorders like Alzheimer's disease (AD).
In summary, NCAM is functional during development and in neuroplastic processes underlying memory formation in mature brain.,
| Ageing and Cd56|| |
CD6 may have a role in senescence and creation of a functionally distinct immunologic environment in old age. Ageing in the immune system leads to contraction of the lymphocyte repertoire causing loss of adaptive immunity with relative preservation of innate immunity. There is a decline in the absolute number of CD4+ and CD8+ T-lymphocytes and B-cells with relative increase in CD56+ NKs, such that the overall lymphocyte count does not change. Thymic involution and a dramatic reduction in the naïve T-cell pool and relative increase in memory T-cells occur. Progressive exhaustion of CD8+ subset causes loss of costimulatory molecules (CD28), shortening of telomeres, and terminal differentiation to end stage.
By monitoring of T-cells senescence, Lemster et al. have shown an age-dependent de novo induction of CD56 in fresh T-cells from blood. These unusual T-cells expressing high levels of Bcl2, p16, and p53, had limited or completely lost ability to undergo cell division. CD56 cross-linking without T-cell receptor (TCR) ligation on CD56+ T-cells resulted in extensive protein phosphorylation, NF-κB activation, Bax down-regulation and production of various humoral factors. Authors proposed that CD56+ T-cells are unique effectors capable of mediating TCR-independent immune cascades and possibly increased protective immunity in the elderly.
| Cd56 in Pregnancy and Abortions|| |
CD56 may facilitate implantation of fertilized ovum in endometrial bed and progression of early phase of pregnancy. The preimplantation endometrium and early pregnancy decidua possess a unique immune environment, characterized by the presence of large numbers of uterine-specific NK-cells (uNKs) (also called decidual-NK), along with progesterone levels and smaller population of macrophages.
The uNKs reach 70–80% of total leukocytes infirst trimester, then start to decline, and return to basal levels at the end of pregnancy. These uNKs consist of CD56high CD16− CD3− type.
When compared with the two major subsets of peripheral blood NK-cells (pbNKs), uNKs have different gene microarray profile with immunomodulatory potential exclusive to uNKs. Although they contain cytotoxic granules and express killer immunoglobulin-like receptor (KIR), they are weakly cytolytic exvivo. Recruitment and functional properties of uNKs are influenced by IL-15 and IL-11, produced by the decidua, and progesterone.,,, Lack of inflammatory and cytotoxic lymphocytes, together with the interactions between uNKs and fetal trophoblasts, create an environment permissive to embryo implantation and good pregnancy outcome.,,,
The causes of spontaneous abortion are mainly chromosomal anomalies (50–60% of early spontaneous abortions); and/or maternal factors., NKs may determine the fate of pregnancy and are important in abortion with normal chromosomes. CD56+ CD16− NKs secrete various cytokines, including macrophage colony-stimulating factor (M-CSF) and granulocyte macrophage-CSF, that promote placental growth. CD56+ 16− 3− NKs in decidua of chromosomally normal abortions were significantly lower than those of chromosomally abnormal abortions.
Among the many KIRs, KIR2DL4 is phylogenetically conserved, nonpolymorphic class Ib, human leukocyte antigen G (the only KIR member expressed by all human NKs).
Yan et al. reveal that KIR2DL4 protein level on pbNKs cells was much higher in normal pregnant women than early recurrent spontaneous abortions patients, indicating KIR2DL4 role in maintaining pregnancy.
A shift of Th1-dominant to Th2-dominant status by fashionable paternal lymphocyte immunization might play a role in maintaining successful pregnancies. However, a systematic review of the literature indicated that more studies are needed to confirm or refute the role of pbNKs or pbNK parameters assessments as a predictive test for screening women who may benefit from immunotherapy.
| Infections and Variable Cd56 Expression on Natural Killer-Cell Subsets|| |
Innate and adaptive immune responses cooperate to protect the host against microbial infections. NK-cells provide a link between innate and adaptive immunity. CD56+ NKs provide innate immunity against microbes. They can lyse tumor and virally transformed target cells without prior sensitization in the early stages of an immune response. NK-mediated pathogen recognition and NKs activation, involves toll-like receptors (TLRs) and activating KIRs. TLRs are germ-line encoded pattern-recognition receptors that recognize pathogens triggering innate responses and shaping subsequent adaptive immune responses. Certain TLRs (TLR1, 2, 4, 5, and 6) are expressed on the cell surface, whereas others (TLR3, 7, 8, and 9) are localized in intracellular compartments (i.e., endosomes). Therefore, their ligands require internalization to generate signals.
NK-cells constitute 10–15% of the circulating lymphocytes and have cytolytic activity against pathogen infected cells. The highest CD56 expression is by NKs of the liver and decidua. Based on cell surface density of CD56 and CD16, NKs are divided into CD56dim CD16+ NKs (more cytotoxic and 90% of blood total NKs) and CD56bright CD16− (~10%) which are immunoregulatory working principally through cytokine production. Although CD56− NKs exist in healthy individuals, but are very low percent of total blood NKs. NK-cell subsets according to CD56 expression differ in surface/cytoplasmic molecules and functional properties [Table 1]. Activated NKs express CD69, while apoptotic NKs express dim annexin-v.
|Table 1: Some differences in surface/cytoplasmic molecules and functional properties of NK-cell subsets according to CD56 expression, |
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Viral infections may have a significant impact on NKs maturation, promoting the expansion of phenotypically and functionally aberrant NK subpopulations. An imbalance of NKs subsets, has been detected in hematopoietic stem cell transplantation (HSCT) recipients for high risk leukemias and experiencing human cytomegalovirus (HCMV) infection/reactivation. Curiously, NKs developing after CMV reactivation may contain "memory-like" or "long-lived" NKs that could exert a potent antileukemia effect. The role of various subsets of NKs in some of the most common infections is summarized in the following paragraphs.
NKs arefirst line of defence against acute viral infections and influence the course of chronic viral infections, like HIV-1 and hepatitis C virus (HCV). Chronic stages of these infections have a negative impact on NKs function and promote the appearance of phenotypically and functionally abnormal NK-cells including CD56 negative NK-cells [Figure 2]. A subset of CD3− CD56− CD16+ NKs subset is highly expanded during chronic HIV-1 infection and a subset of it are CD7+ CD56− CD16+ NK-cells. These are activated mature NKs that may have recently engaged target cells.
|Figure 2: Changes in distribution of peripheral blood natural killer cells subsets (CD56 bright, CD56dim, and CD56−) in patients with acute or chronic HIV/hepatitis C virus infection, pre- and post-antiviral treatment and/or immunotherapy. Variation in the relative size of the CD56−, CD56dim and CD56bright natural killer cell subset after therapy is depicted by arrows. CD56− natural killer cells are increased in numbers during chronic hepatitis C virus or HIV infection. HAART: highly active antiretroviral therapy|
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An aberrant CD56− NKs subset is greatly expanded in HIV-viremia. The number and percentage of CD16+ CD56+ NKs (>90% NKs in healthy adults) are severely decreased even in HIV-seropositive nonAIDS subjects with >800 CD4+ cells/mm 3; and CD16+ CD56− subset, that is rare in healthy adults, is elevated. CD3− CD56dim subset expands in primary HIV infection compared to healthy controls. Tarazona et al. demonstrated the decreased expression of CD56 on peripheral blood CD8bright T-cells from HIV-infected individuals. Low CD56+ NKs may lead to a rapid progression (within 70 months following seroconversion) to AIDS.
Hepatitis C Virus Infection
CD56+ NKs are important in HCV infection. Decreased hepatic CD56+ NKs in late-stage HCV disease may be a risk factor for the development of hepatocellular carcinoma. Paradoxically, increased CD56bright NKs that produce more interferon-gamma (IFN-γ) might contribute to T-cell polarization and liver damage.,
Lin et al. observed that CD3− CD56+ NKs are decreased in HCV-infected patients. Additionally, without pegylated-interferon-alpha (PEG-IFN-α)-2b stimulation, HCV patients had fewer activated bright (CD3− CD56+bright CD69+) and activated dim (CD3− CD56+dim CD69+) NKs compared to controls, suggesting alteration in immunoregulatory and cytotoxic function of NKs. Moreover, dim (CD3− CD56+dim) NK-cell turnover is enhanced in the sustained viral responder patients. By increasing dim NK-cell activation and augmenting NK-cell cytotoxicity through increased perforin/granzyme release, PEG-IFN-α may augment the decline in HCV RNA. Pretreatment higher percentage of CD56− NKs is a predictor of peg-IFN-α and ribavirin treatment failure, and may identify patients likely to benefit from novel combination regimens including HCV protease inhibitors.
Like HIV-1-infected patients, a skewed CD56− NK population with limited polyfunctionality expands in patients with chronic HCV making CD56− NKs a possible cellular immunological biomarker of HCV treatment outcome that merits further investigation.
Björkström et al. reported that CD56− NKs are increased during chronic HCV or HIV infection. Treatment with IFN-α and ribavirin, for chronic HCV, or highly active antiretroviral therapy for chronic HIV, returns the CD56− NKs to levels found in healthy individuals  [Figure 2].
Epstein–Barr Virus Infection
CD56bright NKs controls the primary Epstein–Barr virus (EBV) infection by eliminating infected B-cells and augmenting the antigen-specific T-cell response via release of immunomodulatory cytokines. NKs were significantly elevated up to a month following diagnosis of infectious mononucleosis and increased CD56bright cells with enhanced ability to kill EBV-infected cell lines were observed at diagnosis.
HCMV infection is common when T-cell immunity is impaired like in HIV-infection, congenitally immunodeficient and patients undergoing HSCT. A dramatic expansion of NKG2C+ NKs happens in HCMV (and HIV1) infections. In HSCT recipients, CD56+ NKs maturation is skewed toward highly differentiated stages that look like "memory-like" NKs possibly contributing to the control of HCMV reactivation. In the absence of NKG2C, the activating KIRs may contribute in the control of CMV infections., A reduced risk of HCMV reactivation has been reported in solid organ transplant recipients expressing two or more activating KIRs, HSCT recipient from donors expressing two or more activating KIRs.,
Recent studies suggested a correlation between early HCMV reactivation and reduction of leukemia relapses after allogeneic HSCT in adult patients., A fraction of HCMV-reactivating patients showed an unusual hypofunctional CD56− CD16+ (mostly mature KIR + NKG2A −) NKs subset expansion previously reported in HIV and HCV infections.,
Tuberculosis is another prevalent human disease where CD56+ NK T-cells have role in early eradication of the disease by antituberculous therapy. Veenstra et al. found that high counts of CD3dim/CD56+ NK T-cells at diagnosis correlated significantly with negative sputum culture after 8 weeks of treatment. Interestingly, a higher absolute pbNKs count, which may be the result of an inability of these cells to migrate into infected tissues, was partially indicative of a slow response to treatment.
Increased percentage of CD56bright NKs was found in individuals with positive tuberculin skin test. They are protected from active tuberculosis by the CD56bright NKs secreting high amounts of IFN-γ. A direct interaction with extracellular mycobacteria may induce NK activation and cytokine secretion by these innate cells.,,
Malaria, along with tuberculosis and infection with HIV, is one of the three most important infectious diseases worldwide. Blood CD56+ T-cells are important in the immune response to intracellular pathogens like Plasmodium falciparum and Plasmodium vivax. In both mouse and human models of malaria, NKs are major source of proinflammatory cytokine IFN-γ during the early phase of infection. Watanabe et al. found that the proportion of CD56+ T-cells, CD57+ T-cells, and γδ T-cells (i.e., all unconventional T-cells with NK markers) had increased in early phase of infection with P. falciparum or P. vivax.
| Neuronal Degenerative Disorders|| |
The NCAM, is a key mediator of axonal/dendritic growth, branching, synaptic strength, and plasticity and is important in cognitive function (see above). NCAM has been attributed to susceptibility risk for neuropsychiatric disorders like schizophrenia, bipolar disorder, depression, and anxiety disorder, and AD that have cognitive dysfunction as a core feature. The isoform NCAM180 interacts with cytoskeletal components and may be important in synaptic stability and memory formation. PSA-NCAM is a highly glycosylated form of NCAM that is required for synaptic plasticity and is increased during learning and memory formation., How alterations in NCAM may disrupt normal connectivity leading to cognitive dysfunction is being explored to understand complexities of various neuropsychiatric and neurodegenerative disorders specifically schizophrenia and AD.
Schizophrenia affects approximately 1% of the world's population  with psychosis being the most common clinical feature, but cognitive dysfunction (memory, executive control/information processing, and attention) may be more disabling and can predict long-term outcome., Though environmental risk factors also exist, several genes have been proposed as vulnerability loci, among them modulations in NCAM is also implicated.
In a meta-analysis of schizophrenia susceptibility loci, NCAM was ranked fourth. The reported NCAM modulations in schizophrenia include: Single nucleotide polymorphisms in NCAM, polysialyltransferase ST8Sia II (STX), low PSA-NCAM and high NCAM cleavage.,,,,
Increases in the levels of a soluble NCAM fragments, cleaved from NCAM by ADAM (a disintegrin and metalloprotease) type proteases specifically ADAM10 and ADAM17,,,,, have been correlated with disease severity and duration in schizophrenia.,,,
Mice lacking only NCAM180 display increased lateral ventricles (the most reliable morphological feature in the schizophrenic brain), and learning deficit and prepulse inhibition of acoustic startle;, while mice lacking all isoforms of NCAM have abnormalities in the hippocampus and olfactory bulb, without ventricular enlargement.,,,,
AD, predominantly a disease of the elderly population except rare familial form, is the most common neurodegenerative disease, affecting more than 20 million people worldwide., Affected brain regions are hippocampus, frontal cortex in addition to general brain atrophy. Neurofibrillary plaques and tangles in the brain which are composed of amyloid b and Tau proteins, respectively, are the hallmark features of AD., Total amyloid b levels are important for the progression of AD and resulting cognitive dysfunction., Several NCAM modulations have been reported in in AD including low NCAM, high PSA-NCAM, high NCAM cleavage, low HNK-1 glycosylation, and low NCAM signaling. The dysregulated production of amyloid b and Tau associated with AD also affects NCAM expression and function.
The peptide derivatives of NCAM are currently in clinical trials as a potential treatment for AD. An ideal AD drug would reduce amyloid b and/or Tau levels, foster neuronal connectivity, stop neuron loss, and improve cognition and memory. The FGL peptide is a short NCAM peptide of the FGFR binding site from Glu681-Ala695, which seemingly meets these criteria and FGL may also have curative potential. Experiments suggest that regulating NCAM signaling in the brain may provide a novel treatment possibility for AD.
Targeted inhibition of NCAM cleavage in the brain could help alleviate AD. However, currently available metalloprotease inhibitors produce various nonneuronal side effects such as rheumatoid arthritis (RA), tendonitis, fibroplasias, or exacerbate pulmonary disease or cancer. PSA with NCAM may help in improving plasticity, thereby alleviate the learning and memory deficits ,, and allow axonal growth and synaptogenesis.,
| Fetal Alcohol Spectrum Disorders|| |
Fetal alcohol spectrum disorders (FASDs) are a group of conditions occurring in 1–5/1000 live births of alcoholic mothers, the most common preventable cause of mental retardation in the Western world. Severe cases of FASD shows growth deficiency, neurological abnormalities, and facial malformations. Prenatal ethanol exposure disrupts domain interface between Ig1 and Ig4 of NCAM-L1 causing abnormal neuronal development.
| Paroxysmal Nocturnal Hemoglobinuria|| |
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disease characterized by intravascular hemolysis, increased risk of thrombosis, and variable degrees of pancytopenia. PNH results from an acquired mutation in the X-linked PIG-A gene in the hematopoietic stem cell (HSC), leading to a clone with deficient expression of glycosyl-phosphatidylinositol (GPI)-anchored proteins, especially the complement inhibitors CD59 and CD55 on erythrocytes, causing chronic intravascular hemolysis upon complement activation. The clinical evolution of PNH requires clonal expansion of PIG-A-mutated HSC that may occur as small clone(s) in few healthy individuals. Number of CD8+ T-cells expressing CD56 and activating NKRs increases in PNH which in some cases may exhibit increased lysis of GPI + (vs. GPI −) hematopoietic cells causing cytopenias. However, multiple factors influence whether GPI-dependent lysis occurs.
| Autoimmune Disorders|| |
Multiple sclerosis (MS) is an inflammatory/demyelinating disease of the CNS that is one of the leading causes of neurological disability in young adults. Pathogenetic studies have indicated that autoimmune T-cells targeting myelin components play a crucial role in mediating the inflammatory process, particularly in the early stages of relapsing–remitting MS.
Takahashi et al. demonstrated that NK-cells in MS-remitting type (but not MS-relapsing type) show elevation of IL-5 mRNA and a higher percentage of CD95+ cells among the CD56+ NK-cells,, indicating that NK-cells may regulate activation of autoimmune memory T-cells in an antigen nonspecific fashion to maintain the clinical remission in “CD95+ NK-high” MS patients., When MS was treated with IFN-β, an expansion of CD56bright NK-cells was observed with a concomitant decrease of CD56dim cells after 12 months of treatment.
The search for new therapies in the recent past has focused on agents that affect lymphocyte function. Daclizumab, a humanized mAb that blocks the IL-2 binding site on the IL-2Rα chain (CD25), is among these novel agents. Administration of daclizumab strongly reduces brain inflammation in MS patients. Daclizumab therapy was associated with a gradual decline in circulating CD4+ and CD8+ T-cells and significant expansion of CD56bright NK-cells in >vivo, and this effect correlated highly with the treatment response.,
Pertinently, because the regulatory properties of the newly described RUNX1 splice variants extend beyond CD56 to other RUNX1 target genes, the recent results of Gattenloehner et al. could be therapeutically relevant for RUNX1-related gene regulation in a broad spectrum of clinical settings, including autoimmune diseases like MS.,,,
Rheumatoid Arthritis, Systemic Lupus Erythematosus, and Autoimmune Thyroid Disorders
Although the identity of antigens driving T-cell oligoclonality in RA remains elusive, the physiologic inflammatory environment of RA is clearly permissive of the persistent oligoclonal expansion of CD28− T-cells that have acquired the prototypic NK receptor CD56. These CD56+ T-cells have features of senescence and are potential targets for therapy. In RA, the synovial fluid of the patients almost exclusively contains CD56bright KIR − NK-cells.
In systemic lupus erythematosus, increased proportion of CD56bright NK-cells are described regardless of disease activity.
CD56 has been detected in the thyroid follicular cells (thyrocytes) immunohistologically. In autoimmune disorders thyroid cells express the 140- and 180-kD forms of NCAM (not the 120 kD NCAM isoform which is predominantly expressed in normal and well differentiated tissues). CD56 expression in thyrocytes of surgical specimens was found to be increased in 11/17 (64%) of Graves', in 5/25 (20%) of multinodular goitre and in occasional adenoma glands. It was often seen in areas infiltrated by macrophages.
In another pilot study of thyroid FNAC, 96% of the samples positive for malignancy did not show any follicular cell with CD56 expression. CD56 may be an additional marker for ruling out papillary thyroid carcinoma (PTC) especially when used in conjunction with HBME-1 and Galectin-3.
| Cd56 Isoforms Expression in Malignancies and Therapeutic Implications|| |
Among all diseases, the role of CD56 in cancer is perhaps the most extensively studied one, and due to great heterogeneity of disorders and huge available data, a detailed review of it, along with anti-CD56 antibody therapies and NK-cell based cellular therapies, will be covered later elsewhere. Only the main highlights of the role of CD56 in cancer will be briefly covered here.
CD56 is variably expressed on many tumor cells [Table 2]. CD56 has a clear function in homotypic binding to CD56 molecules on other cells. Alternative mRNA splicing results in three major isoforms. A 120 kDa NCAM isoform connected by a GPI anchor to the cell membrane which is predominantly expressed in normal and well differentiated tissues. The 140 and 180 kDa isoforms (which contains a transmembrane domain) are found predominantly in less differentiated embryonic or malignant cell types, thereby expression of NCAM shifts from the NCAM120 isoform to the NCAM140 and NCAM180 isoforms in cancer.,,
Many recent reports correlate CD56 overexpression with an aggressive clinical phenotype in a variety of hematological malignancies, including acute myeloid leukemia (both in acute promyelocytic leukemia [APL] and non-APL),,,,,,,,,,,, acute lymphoblastic leukemia,,, and Anaplastic large cell lymphoma. Whereas CD56 expression is also reported in majority of cases of multiple myeloma,,, NK-cell leukemia and lymphomas, γδ T-cell lymphomas,, various cutaneous lymphomas, T-cell large granular lymphocyte leukemia (aggressive forms),, and blastic plasmacytoid dendritic cell neoplasm.,, In myelodysplastic syndromes patients widespread numerical, structural and functional NK-cell defects have been recently reported; and deficiency of functionally competent NK-cells might contribute to disease progression through impaired immune surveillance.
Several common solid tumors such as colorectal carcinoma with brain metastasis, small cell lung cancer (SCLC),,,,,, metastatic renal cancer, melanoma, neuroblastoma,,, rhabdomyosarcoma,, paraganglioma, pheochromocytoma, and brain tumors such as astrocytoma,, Ewing sarcoma, primary gastrointestinal leiomyomas, small cell carcinoma of esophagus, gastrointestinal stromal tumors, and rare malignant neuroendocrine tumors like Merkel cell carcinoma also express CD56 frequently. The reported frequencies in selected malignancies are summarized in [Table 2]. Malignancies expressing CD56 are usually aggressive, with more potential for metastasis and extramedullary/CNS involvement, and may respond to new CD56-linked targeted therapies.
From the spectrum of existing anti-CD56 compounds, an antibody–drug conjugates consisting of Anti-CD56 antibody attached to a potent antimicrotubular cytotoxic agent DM-1 (a maytasinoid effector molecule) is Lorvotuzumab mertansine (LM, also known as IMGN901).,, Once bound to CD56, IMGN901 is internalized into a cancer cell and its DM1 is released to cause cell death via inhibition of tubulin polymerization. Overall it is the most advanced anti-CD56 therapeutic strategy and clinical usage has produced promising results in trials setting both as single agent (in many cancers), and in combination with chemotherapy (for myeloma and SCLC).,,,,,,,,,,,,,,,,,,
Authors would like to thank for assistance provided by:
- Dr. Mohammad Yunus, Associate Professor and Hematopathologist, Department of Pathology King Fahd Hospital of the University, College of Medicine University of Dammam, Dammam, Saudi Arabia (for professionally reviewing and editing the text)
- Mr. AbdulRehman Zia Zaidi, Final year MBBS student at Alfaisal University, Riyadh, Saudi Arabia (in preparation of this manuscript).
Financial Support and Sponsorship
Conflicts of Interest
There are no conflicts of interest.
| References|| |
Reyes AA, Small SJ, Akeson R. At least 27 alternatively spliced forms of the neural cell adhesion molecule mRNA are expressed during rat heart development. Mol Cell Biol 1991;11:1654-61.
Crossin KL, Krushel LA. Cellular signaling by neural cell adhesion molecules of the immunoglobulin superfamily. Dev Dyn 2000;218:260-79.
Kasper C, Rasmussen H, Kastrup JS, Ikemizu S, Jones EY, Berezin V, et al.
Structural basis of cell-cell adhesion by NCAM. Nat Struct Biol 2000;7:389-93.
Rutishauser U. Polysialic acid and the regulation of cell interactions. Curr Opin Cell Biol 1996;8:679-84.
Carnaud C, Lee D, Donnars O, Park SH, Beavis A, Koezuka Y, et al.
Cutting edge: Cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J Immunol 1999;163:4647-50.
Jin L, Hemperly JJ, Lloyd RV. Expression of neural cell adhesion molecule in normal and neoplastic human neuroendocrine tissues. Am J Pathol 1991;138:961-9.
Fusaoka E, Inoue T, Mineta K, Agata K, Takeuchi K. Structure and function of primitive immunoglobulin superfamily neural cell adhesion molecules: A lesson from studies on planarian. Genes Cells 2006;11:541-55.
Edelman GM, Jones FS. Developmental control of N-CAM expression by Hox and Pax gene products. Philos Trans R Soc Lond B Biol Sci 1995;349:305-12.
Zhou FQ, Zhong J, Snider WD. Extracellular crosstalk: When GDNF meets N-CAM. Cell 2003;113:814-5.
Paratcha G, Ledda F, Ibáñez CF. The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands. Cell 2003;113:867-79.
Conboy L, Bisaz R, Markram K, Sandi C. Role of NCAM in emotion and learning. Adv Exp Med Biol 2010;663:271-96.
Maness PF, Schachner M. Neural recognition molecules of the immunoglobulin superfamily: Signaling transducers of axon guidance and neuronal migration. Nat Neurosci 2007;10:19-26.
Plappert CF, Schachner M, Pilz PK. Neural cell adhesion molecule (NCAM-/-) null mice show impaired sensitization of the startle response. Genes Brain Behav 2006;5:46-52.
Neiiendam JL, Køhler LB, Christensen C, Li S, Pedersen MV, Ditlevsen DK, et al.
An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons. J Neurochem 2004;91:920-35.
Cambon K, Hansen SM, Venero C, Herrero AI, Skibo G, Berezin V, et al.
A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation. J Neurosci 2004;24:4197-204.
Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol 2007;211:144-56.
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al.
Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N
Y Acad Sci 2000;908:244-54.
Lemster BH, Michel JJ, Montag DT, Paat JJ, Studenski SA, Newman AB, et al.
Induction of CD56 and TCR-independent activation of T cells with aging. J Immunol 2008;180:1979-90.
Croy BA, van den Heuvel MJ, Borzychowski AM, Tayade C. Uterine natural killer cells: A specialized differentiation regulated by ovarian hormones. Immunol Rev 2006;214:161-85.
Bulmer JN, Lash GE. Human uterine natural killer cells: A reappraisal. Mol Immunol 2005;42:511-21.
Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, et al.
Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003;198:1201-12.
Verma S, Hiby SE, Loke YW, King A. Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15. Biol Reprod 2000;62:959-68.
Ain R, Trinh ML, Soares MJ. Interleukin-11 signaling is required for the differentiation of natural killer cells at the maternal-fetal interface. Dev Dyn 2004;231:700-8.
Keskin DB, Allan DS, Rybalov B, Andzelm MM, Stern JN, Kopcow HD, et al.
TGFbeta promotes conversion of CD16 peripheral blood NK cells into CD16+NK cells with similarities to decidual NK cells. Proc Natl Acad Sci U S A 2007;104:3378-83.
Carlino C, Stabile H, Morrone S, Bulla R, Soriani A, Agostinis C, et al.
Recruitment of circulating NK cells through decidual tissues: A possible mechanism controlling NK cell accumulation in the uterus during early pregnancy. Blood 2008;111:3108-15.
King A, Hiby SE, Gardner L, Joseph S, Bowen JM, Verma S, et al.
Recognition of trophoblast HLA class I molecules by decidual NK cell receptors – A review. Placenta 2000;21 Suppl A: S81-5.
Jones RL, Stoikos C, Findlay JK, Salamonsen LA. TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction 2006;132:217-32.
Yamamoto T, Takahashi Y, Kase N, Mori H. Role of decidual natural killer (NK) cells in patients with missed abortion: Differences between cases with normal and abnormal chromosome. Clin Exp Immunol 1999;116:449-52.
Cunningham FG, Gant NF, Leveno KJ, Gilstrap III LC, Hauth JC, Wenstrom KD. Abortion: Reproductive success and failure. In: Cunningam FG, MacDonald PC, editors. Williams Obstetrics. 20th
ed. Tokyo: Prentice Hall; 1997. p. 579-605.
Saito S, Nishikawa K, Morii T, Enomoto M, Narita N, Motoyoshi K, et al.
Cytokine production by CD16-CD56bright natural killer cells in the human early pregnancy decidua. Int Immunol 1993;5:559-63.
Yan WH, Lin A, Chen BG, Zhou MY, Dai MZ, Chen XJ, et al.
Possible roles of KIR2DL4 expression on uNK cells in human pregnancy. Am J Reprod Immunol 2007;57:233-42.
Wilczynski JR, Radwan P, Tchórzewski H, Banasik M. Immunotherapy of patients with recurrent spontaneous miscarriage and idiopathic infertility: Does the immunization-dependent Th2 cytokine overbalance really matter? Arch Immunol Ther Exp (Warsz) 2012;60:151-60.
Tang AW, Alfirevic Z, Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: A systematic review. Hum Reprod 2011;26:1971-80.
Della Chiesa M, Marcenaro E, Sivori S, Carlomagno S, Pesce S, Moretta A. Human NK cell response to pathogens. Semin Immunol 2014;26:152-60.
Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and related disorders. Oncologist 2004;9:247-58.
Björkström NK, Ljunggren HG, Sandberg JK. CD56 negative NK cells: Origin, function, and role in chronic viral disease. Trends Immunol 2010;31:401-6.
Jacobs R, Hintzen G, Kemper A, Beul K, Kempf S, Behrens G, et al.
CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells. Eur J Immunol 2001;31:3121-7.
Milush JM, López-Vergès S, York VA, Deeks SG, Martin JN, Hecht FM, et al.
CD56negCD16+NK cells are activated mature NK cells with impaired effector function during HIV-1 infection. Retrovirology 2013;10:158.
Titanji K, Sammicheli S, De Milito A, Mantegani P, Fortis C, Berg L, et al.
Altered distribution of natural killer cell subsets identified by CD56, CD27 and CD70 in primary and chronic human immunodeficiency virus-1 infection. Immunology 2008;123:164-70.
Tarazona R, DelaRosa O, Casado JG, Torre-Cisneros J, Villanueva JL, Galiani MD, et al.
NK-associated receptors on CD8 T cells from treatment-naive HIV-infected individuals: Defective expression of CD56. AIDS 2002;16:197-200.
Bruunsgaard H, Pedersen C, Skinhøj P, Pedersen BK. Clinical progression of HIV infection: Role of NK cells. Scand J Immunol 1997;46:91-5.
Lin AW, Gonzalez SA, Cunningham-Rundles S, Dorante G, Marshall S, Tignor A, et al.
CD56(+dim) and CD56(+bright) cell activation and apoptosis in hepatitis C virus infection. Clin Exp Immunol 2004;137:408-16.
Golden-Mason L, Madrigal-Estebas L, McGrath E, Conroy MJ, Ryan EJ, Hegarty JE, et al.
Altered natural killer cell subset distributions in resolved and persistent hepatitis C virus infection following single source exposure. Gut 2008;57:1121-8.
Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: An important NK cell subset. Immunology 2009;126:458-65.
Gonzalez VD, Falconer K, Björkström NK, Blom KG, Weiland O, Ljunggren HG, et al.
Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: Correlation with outcome of pegylated IFN-alpha and ribavirin treatment. J Immunol 2009;183:6612-8.
Williams H, McAulay K, Macsween KF, Gallacher NJ, Higgins CD, Harrison N, et al.
The immune response to primary EBV infection: A role for natural killer cells. Br J Haematol 2005;129:266-74.
Della Chiesa M, Falco M, Bertaina A, Muccio L, Alicata C, Frassoni F, et al.
Human cytomegalovirus infection promotes rapid maturation of NK cells expressing activating killer Ig-like receptor in patients transplanted with NKG2C-/- umbilical cord blood. J Immunol 2014;192:1471-9.
Cook M, Briggs D, Craddock C, Mahendra P, Milligan D, Fegan C, et al.
Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood 2006;107:1230-2.
Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, et al
. Early human cytomegalovirus replication after transplant is associated with a decreased relapse-risk: Evidence for a putative virus-versus-leukemia effect in AML patients. Blood 2011;118:1402-12.
Manjappa S, Bhamidipati PK, Stokerl-Goldstein KE, Dipersio JF, Uy GL, Westervelt P, et al
. Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen. Biol Blood Marrow Transplant 2014;20:46-52.
Della Chiesa M, Falco M, Podestà M, Locatelli F, Moretta L, Frassoni F, et al.
Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: A role for human cytomegalovirus? Blood 2012;119:399-410.
Veenstra H, Baumann R, Carroll NM, Lukey PT, Kidd M, Beyers N, et al.
Changes in leucocyte and lymphocyte subsets during tuberculosis treatment; prominence of CD3dimCD56+natural killer T cells in fast treatment responders. Clin Exp Immunol 2006;145:252-60.
Barcelos W, Sathler-Avelar R, Martins-Filho OA, Carvalho BN, Guimarães TM, Miranda SS, et al.
Natural killer cell subpopulations in putative resistant individuals and patients with active Mycobacterium tuberculosis infection. Scand J Immunol 2008;68:92-102.
Marcenaro E, Ferranti B, Falco M, Moretta L, Moretta A. Human NK cells directly recognize Mycobacterium bovis via TLR2 and acquire the ability to kill monocyte-derived DC. Int Immunol 2008;20:1155-67.
Roetynck S, Baratin M, Johansson S, Lemmers C, Vivier E, Ugolini S. Natural killer cells and malaria. Immunol Rev 2006;214:251-63.
Watanabe H, Weerasinghe A, Miyaji C, Sekikawa H, Toyabe S, Mannor MK, et al.
Expansion of unconventional T cells with natural killer markers in malaria patients. Parasitol Int 2003;52:61-70.
Leann HB, Patricia FM. NCAM in neuropsychiatric and neurodegenerative disorders. In: Structure and Function of the Neural Cell Adhesion Molecule NCAM-Advances in Experimental Medicine and Biology (Series). Ch. 19, Vol. 663. New York: Springer; 2010. p. 299-317.
Cremer H, Chazal G, Lledo PM, Rougon G, Montaron MF, Mayo W, et al.
PSA-NCAM: An important regulator of hippocampal plasticity. Int J Dev Neurosci 2000;18:213-20.
Freedman R. Schizophrenia. N Engl J Med 2003;349:1738-49.
Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005;6:312-24.
Lewis DA, González-Burgos G. Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 2008;33:141-65.
Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, et al.
Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003;73:34-48.
Maziade M, Roy MA, Chagnon YC, Cliche D, Fournier JP, Montgrain N, et al.
Shared and specific susceptibility loci for schizophrenia and bipolar disorder: A dense genome scan in Eastern Quebec families. Mol Psychiatry 2005;10:486-99.
Lindholm E, Aberg K, Ekholm B, Pettersson U, Adolfsson R, Jazin EE. Reconstruction of ancestral haplotypes in a 12-generation schizophrenia pedigree. Psychiatr Genet 2004;14:1-8.
Tao R, Li C, Zheng Y, Qin W, Zhang J, Li X, et al.
Positive association between SIAT8B and schizophrenia in the Chinese Han population. Schizophr Res 2007;90:108-14.
Sullivan PF, Keefe RS, Lange LA, Lange EM, Stroup TS, Lieberman J, et al.
NCAM1 and neurocognition in schizophrenia. Biol Psychiatry 2007;61:902-10.
Hinkle CL, Diestel S, Lieberman J, Maness PF. Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). J Neurobiol 2006;66:1378-95.
Hübschmann MV, Skladchikova G, Bock E, Berezin V. Neural cell adhesion molecule function is regulated by metalloproteinase-mediated ectodomain release. J Neurosci Res 2005;80:826-37.
Kalus I, Bormann U, Mzoughi M, Schachner M, Kleene R. Proteolytic cleavage of the neural cell adhesion molecule by ADAM17/TACE is involved in neurite outgrowth. J Neurochem 2006;98:78-88.
Kärkkäinen I, Rybnikova E, Pelto-Huikko M, Huovila AP. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. Mol Cell Neurosci 2000;15:547-60.
Lyons F, Martin ML, Maguire C, Jackson A, Regan CM, Shelley RK. The expression of an N-CAM serum fragment is positively correlated with severity of negative features in type II schizophrenia. Biol Psychiatry 1988;23:769-75.
Vawter MP, Usen N, Thatcher L, Ladenheim B, Zhang P, VanderPutten DM, et al.
Characterization of human cleaved N-CAM and association with schizophrenia. Exp Neurol 2001;172:29-46.
Honer WG, Falkai P, Young C, Wang T, Xie J, Bonner J, et al.
Cingulate cortex synaptic terminal proteins and neural cell adhesion molecule in schizophrenia. Neuroscience 1997;78:99-110.
Gilmore JH, van Tol J, Kliewer MA, Silva SG, Cohen SB, Hertzberg BS, et al.
Mild ventriculomegaly detected in utero
with ultrasound: Clinical associations and implications for schizophrenia. Schizophr Res 1998;33:133-40.
Wood GK, Tomasiewicz H, Rutishauser U, Magnuson T, Quirion R, Rochford J, et al.
NCAM-180 knockout mice display increased lateral ventricle size and reduced prepulse inhibition of startle. Neuroreport 1998;9:461-6.
Stork O, Welzl H, Wolfer D, Schuster T, Mantei N, Stork S, et al.
Recovery of emotional behaviour in neural cell adhesion molecule (NCAM) null mutant mice through transgenic expression of NCAM180. Eur J Neurosci 2000;12:3291-306.
Rafuse VF, Polo-Parada L, Landmesser LT. Structural and functional alterations of neuromuscular junctions in NCAM-deficient mice. J Neurosci 2000;20:6529-39.
Chazal G, Durbec P, Jankovski A, Rougon G, Cremer H. Consequences of neural cell adhesion molecule deficiency on cell migration in the rostral migratory stream of the mouse. J Neurosci 2000;20:1446-57.
Stork O, Welzl H, Wotjak CT, Hoyer D, Delling M, Cremer H, et al.
Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. J Neurobiol 1999;40:343-55.
Bukalo O, Fentrop N, Lee AY, Salmen B, Law JW, Wotjak CT, et al.
Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus. J Neurosci 2004;24:1565-77.
Goedert M, Spillantini MG. A century of Alzheimer's disease. Science 2006;314:777-81.
Yaari R, Corey-Bloom J. Alzheimer's disease. Semin Neurol 2007;27:32-41.
Klementiev B, Novikova T, Novitskaya V, Walmod PS, Dmytriyeva O, Pakkenberg B, et al.
A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35. Neuroscience 2007;145:209-24.
Moss ML, Bartsch JW. Therapeutic benefits from targeting of ADAM family members. Biochemistry 2004;43:7227-35.
Muller D, Djebbara-Hannas Z, Jourdain P, Vutskits L, Durbec P, Rougon G, et al.
Brain-derived neurotrophic factor restores long-term potentiation in polysialic acid-neural cell adhesion molecule-deficient hippocampus. Proc Natl Acad Sci U S A 2000;97:4315-20.
Stoenica L, Senkov O, Gerardy-Schahn R, Weinhold B, Schachner M, Dityatev A.In vivo
synaptic plasticity in the dentate gyrus of mice deficient in the neural cell adhesion molecule NCAM or its polysialic acid. Eur J Neurosci 2006;23:2255-64.
Sandi C, Merino JJ, Cordero MI, Kruyt ND, Murphy KJ, Regan CM. Modulation of hippocampal NCAM polysialylation and spatial memory consolidation by fear conditioning. Biol Psychiatry 2003;54:599-607.
Brocco MA, Frasch AC. Interfering polysialyltransferase ST8SiaII/STX mRNA inhibits neurite growth during early hippocampal development. FEBS Lett 2006;580:4723-6.
Dityatev A, Dityateva G, Sytnyk V, Delling M, Toni N, Nikonenko I, et al.
Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses. J Neurosci 2004;24:9372-82.
Hoyme HE, May PA, Kalberg WO, Kodituwakku P, Gossage JP, Trujillo PM, et al.
A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: Clarification of the 1996 institute of medicine criteria. Pediatrics 2005;115:39-47.
Arevalo E, Shanmugasundararaj S, Wilkemeyer MF, Dou X, Chen S, Charness ME, et al.
An alcohol binding site on the neural cell adhesion molecule L1. Proc Natl Acad Sci U S A 2008;105:371-5.
Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. PIG-A mutations in normal hematopoiesis. Blood 2005;105:3848-54.
van Bijnen ST, Withaar M, Preijers F, van der Meer A, de Witte T, Muus P, et al.
T cells expressing the activating NK-cell receptors KIR2DS4, NKG2C and NKG2D are elevated in paroxysmal nocturnal hemoglobinuria and cytotoxic toward hematopoietic progenitor cell lines. Exp Hematol 2011;39:751-62.e1-3.
Steinman L. Multiple sclerosis: A two-stage disease. Nat Immunol 2001;2:762-4.
Takahashi K, Miyake S, Kondo T, Terao K, Hatakenaka M, Hashimoto S, et al.
Natural killer type 2 bias in remission of multiple sclerosis. J Clin Invest 2001;107:R23-9.
Takahashi K, Aranami T, Endoh M, Miyake S, Yamamura T. The regulatory role of natural killer cells in multiple sclerosis. Brain 2004;127(Pt 9):1917-27.
Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, Waldmann TA, et al.
Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006;103:5941-6.
Gattenloehner S, Chuvpilo S, Langebrake C, Reinhardt D, Müller-Hermelink HK, Serfling E, et al.
Novel RUNX1 isoforms determine the fate of acute myeloid leukemia cells by controlling CD56 expression. Blood 2007;110:2027-33.
Michel JJ, Turesson C, Lemster B, Atkins SR, Iclozan C, Bongartz T, et al.
CD56-expressing T cells that have features of senescence are expanded in rheumatoid arthritis. Arthritis Rheum 2007;56:43-57.
Vargas F, Tolosa E, Sospedra M, Catálfamo M, Lucas-Martín A, Obiols G, et al.
Characterization of neural cell adhesion molecule (NCAM) expression in thyroid follicular cells: Induction by cytokines and over-expression in autoimmune glands. Clin Exp Immunol 1994;98:478-88.
Bizzarro T, Martini M, Marrocco C, D'Amato D, Traini E, Lombardi CP, et al.
The role of CD56 in thyroid fine needle aspiration cytology: A Pilot study performed on liquid based cytology. PLoS One 2015;10:e0132939.
Bourne SP, Patel K, Walsh F, Popham CJ, Coakham HB, Kemshead JT. A monoclonal antibody (ERIC-1), raised against retinoblastoma, that recognizes the neural cell adhesion molecule (NCAM) expressed on brain and tumours arising from the neuroectoderm. J Neurooncol 1991;10:111-9.
Abbott JJ, Amirkhan RH, Hoang MP. Malignant melanoma with a rhabdoid phenotype: Histologic, immunohistochemical, and ultrastructural study of a case and review of the literature. Arch Pathol Lab Med 2004;128:686-8.
Roy DC, Ouellet S, Le Houillier C, Ariniello PD, Perreault C, Lambert JM. Elimination of neuroblastoma and small-cell lung cancer cells with an anti-neural cell adhesion molecule immunotoxin. J Natl Cancer Inst 1996 21;88:1136-45.
Mechtersheimer G, Staudter M, Möller P. Expression of the natural killer cell-associated antigens CD56 and CD57 in human neural and striated muscle cells and in their tumors. Cancer Res 1991;51:1300-7.
Hirano T, Hirohashi S, Kunii T, Noguchi M, Shimosato Y, Hayata Y. Quantitative distribution of cluster 1 small cell lung cancer antigen in cancerous and non-cancerous tissues, cultured cells and sera. Jpn J Cancer Res 1989;80:348-55.
Doria MI Jr, Montag AG, Franklin WA. Immunophenotype of small cell lung carcinoma. Expression of NKH-1 and transferrin receptor and absence of most myeloid antigens. Cancer 1988;62:1939-45.
Ash S, Luria D, Cohen IJ, Goshen Y, Toledano H, Issakov J, et al.
Excellent prognosis in a subset of patients with Ewing sarcoma identified at diagnosis by CD56 using flow cytometry. Clin Cancer Res 2011;17:2900-7.
Assaf C, Gellrich S, Whittaker S, Robson A, Cerroni L, Massone C, et al.
CD56-positive haematological neoplasms of the skin: A multicentre study of the Cutaneous lymphoma project group of the European organisation for research and treatment of cancer. J Clin Pathol 2007;60:981-9.
Wlodarska I, Martin-Garcia N, Achten R, De Wolf-Peeters C, Pauwels P, Tulliez M, et al.
Fluorescence in situ
hybridization study of chromosome 7 aberrations in hepatosplenic T-cell lymphoma: Isochromosome 7q as a common abnormality accumulating in forms with features of cytologic progression. Genes Chromosomes Cancer 2002;33:243-51.
Gentile TC, Uner AH, Hutchison RE, Wright J, Ben-Ezra J, Russell EC, et al.
CD3+, CD56+aggressive variant of large granular lymphocyte leukemia. Blood 1994;84:2315-21.
Daniel L, Bouvier C, Chetaille B, Gouvernet J, Luccioni A, Rossi D, et al.
Neural cell adhesion molecule expression in renal cell carcinomas: Relation to metastatic behavior. Hum Pathol 2003;34:528-32.
Agaimy A, Wünsch PH. Distribution of neural cell adhesion molecule (NCAM/CD56) in gastrointestinal stromal tumours and their intra-abdominal mesenchymal mimics. J Clin Pathol 2008;61:499-503.
Ramsay AD, Bates AW, Williams S, Sebire NJ. Variable antigen expression in hepatoblastomas. Appl Immunohistochem Mol Morphol 2008;16:140-7.
Aryal G, Sawabe M, Arai T, Kimula Y, Koike M, Takubo K, et al.
Value of CK14 and CD56 immunostaining in distinguishing small cell carcinoma from squamous cell carcinoma of the esophagus. Nepal Med Coll J 2006;8:75-81.
Carrigan CN, Xu S, Zhao Y, Testa N, Gabriel R, O'Keefe J, et al
. The antigen target of lorvotuzumab mertansine (IMGN901), CD56, is expressed at significant levels in Merkel cell carcinoma (MCC). Proc Am Assoc Cancer Res 2010;51. [Abstr. 5335].
Kurokawa M, Maeda S, Nishida T, Nakayama F, Amano M, Ogata K, et al.
CD56: A Useful Marker for Diagnosing Merkel Cell Carcinoma Abstract # 0306. Available from: http://www.elsevier.com/framework_products/promis_misc/descsidabs05.pdf. [Last accessed on 2015 Sep 09 ].
Tassone P, Gozzini A, Goldmacher V, Shammas MA, Whiteman KR, Carrasco DR, et al
. In vitro
and in vivo
activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+multiple myeloma cells. Cancer Res 2004;64:4629-36.
Chang H, Samiee S, Yi QL. Prognostic relevance of CD56 expression in multiple myeloma: A study including 107 cases treated with high-dose melphalan-based chemotherapy and autologous stem cell transplant. Leuk Lymphoma 2006;47:43-7.
Kaiser U, Jaques G, Havemann K, Auerbach B. Serum NCAM: A potential new prognostic marker for multiple myeloma. Blood 1994;83:871-3.
Ferrara F, Morabito F, Martino B, Specchia G, Liso V, Nobile F, et al.
CD56 expression is an indicator of poor clinical outcome in patients with acute promyelocytic leukemia treated with simultaneous all-trans-retinoic acid and chemotherapy. J Clin Oncol 2000;18:1295-300.
Raspadori D, Damiani D, Lenoci M, Rondelli D, Testoni N, Nardi G, et al.
CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis. Leukemia 2001;15:1161-4.
Zheng J, Wang X, Hu Y, Yang J, Liu J, He Y, et al.
A correlation study of immunophenotypic, cytogenetic, and clinical features of 180 AML patients in China. Cytometry B Clin Cytom 2008;74:25-9.
Baer MR, Stewart CC, Lawrence D, Arthur DC, Byrd JC, Davey FR, et al.
Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t (8;21)(q22;q22). Blood 1997;90:1643-8.
Daniels JT, Davis BJ, Houde-McGrail L, Byrd JC. Clonal selection of CD56+ t(8;21) AML blasts: Further suggestion of the adverse clinical significance of this biological marker? Br J Haematol 1999;107:381-3.
Yang DH, Lee JJ, Mun YC, Shin HJ, Kim YK, Cho SH, et al.
Predictable prognostic factor of CD56 expression in patients with acute myeloid leukemia with t(8:21) after high dose cytarabine or allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007;82:1-5.
Sainty D, Liso V, Cantù-Rajnoldi A, Head D, Mozziconacci MJ, Arnoulet C, et al
. A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Blood 2000;96:1287-96.
Montesinos P, Rayón C, Vellenga E, Brunet S, González J, González M, et al.
Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. Blood 2011;117:1799-805.
Itoh S, Sugawara T, Enomoto S, Ono Y, Numaoka H, Utsugisawa T, et al.
Clonal evolution of blasts in an elderly patient with CD56(+) relapsed acute promyelocytic leukemia. Am J Hematol 2002;69:59-63.
Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Yamauchi T, et al.
Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts. Cancer Sci 2014;105:97-104.
Ikushima S, Yoshihara T, Matsumura T, Misawa S, Morioka Y, Hibi S, et al.
Expression of CD56/NCAM on hematopoietic malignant cells. A useful marker for acute monocytic and megakaryocytic leukemias. Int J Hematol 1991;54:395-403.
Paietta E, Neuberg D, Richards S, Bennett JM, Han L, Racevskis J, et al.
Rare adult acute lymphocytic leukemia with CD56 expression in the ECOG experience shows unexpected phenotypic and genotypic heterogeneity. Am J Hematol 2001;66:189-96.
Montero I, Rios E, Parody R, Perez-Hurtado JM, Martin-Noya A, Rodriguez JM. CD56 in T-cell acute lymphoblastic leukaemia: A malignant transformation of an early myeloid-lymphoid progenitor? Haematologica 2003;88:ELT26.
Ravandi F, Cortes J, Estrov Z, Thomas D, Giles FJ, Huh YO, et al.
CD56 expression predicts occurrence of CNS disease in acute lymphoblastic leukemia. Leuk Res 2002;26:643-9.
Crnic I, Strittmatter K, Cavallaro U, Kopfstein L, Jussila L, Alitalo K, et al.
Loss of neural cell adhesion molecule induces tumor metastasis by up-regulating lymphangiogenesis. Cancer Res 2004;64:8630-8.
Cavallaro U, Christofori G. Multitasking in tumor progression: Signaling functions of cell adhesion molecules. Ann N
Y Acad Sci 2004;1014:58-66.
Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004;4:118-32.
Suzuki R, Kagami Y, Takeuchi K, Kami M, Okamoto M, Ichinohasama R, et al.
Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype. Blood 2000;96:2993-3000.
Chanan-Khan AA, Jagannath S, Schlossmann R, Fram R, Falzone RM, Ruberti MF, et al
. Phase I study of BB-10901 (huN901-DM1) in patients with relapsed and relapsed/refractory CD56-positive multiple myeloma, Blood 2005;108:3574.
Berdeja JG, Ailawadhi S, Weitman SD, Zildjian S, O'Leary JJ, O'Keeffe J, et al
. Phase I study of lorvotuzumab mertansine (LM, IMGN901) in combination with lenalidomide (Len) and dexamethasone (Dex) in patients with CD56-positive relapsed or relapsed/refractory multiple myeloma (MM). J Clin Oncol 2011;29. [Abstr. 8013].
Riaz W, Zhang L, Horna P, Sokol L. Blastic plasmacytoid dendritic cell neoplasm: Update on molecular biology, diagnosis, and therapy. Cancer Control 2014;21:279-89.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al
. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th
ed. Lyon, France: IARC Press; 2008.
Garnache-Ottou F, Feuillard J, Ferrand C, Biichle S, Trimoreau F, Seilles E, et al.
Extended diagnostic criteria for plasmacytoid dendritic cell leukaemia. Br J Haematol 2009;145:624-36.
Hejazi M, Manser AR, Fröbel J, Kündgen A, Zhao X, Schönberg K, et al.
Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes. Haematologica 2015;100:643-52.
Onodera H, Nagayama S, Tachibana T, Fujimoto A, Imamura M. Brain metastasis from colorectal cancer. Int J Colorectal Dis 2005;20:57-61.
Fossella F, Woll PJ, Lorigan P, Tolcher A, O'Brien M, O'Keeffe J, et al
. Clinical experience of IMGN901 (BB-10901) in patients with small cell lung carcinoma. J Thorac Oncol 2009;4 Suppl 9. [Abstr. 6327. (PD4.3.5)].
Fossella F, McCann J, Tolcher A, Xie H, Hwang LL, Carr C, et al
. Phase II trial of BB10901 (huN901-DM1) given weekly for four consecutive weeks every 6 weeks in patients with relapsed SCLC and CD56-positive small cell carcinoma. In Grunberg SM, editor. Proceedings of the American Society of Clinical Oncology. Orlando: American Society of Clinical Oncology; 2005. p. 660s.
Fossella FV, Tolcher A, Elliott M, Lambert JM, Lu R, Zinner R, et al
. Phase I trial of the monoclonal antibody conjugate, BB10901, for relapsed/refractory small cell lung cancer (SCLC) and other neuroendocrine (NE) tumors. Am Soc Clin Oncol 2002. [Abstract no. 1232].
Lambert JM. Drug-conjugated antibodies for the treatment of cancer. Br J Clin Pharmacol 2013;76:248-62.
Jensen M, Berthold F. Targeting the neural cell adhesion molecule in cancer. Cancer Lett 2007;258:9-21.
Smith SV. Technology evaluation: HuN901-DM1, ImmunoGen. Curr Opin Mol Ther 2005;7:394-401.
Fosella FV, McCann J, Tolcher A, Xie H, Hwang L, Carr C, et al
. Phase II trial of BB-10901 (huN901-DM1) given weekly for four consecutive weeks every 6 weeks in patients with relapsed SCLS and CD56-positive small cell carcinoma. J Clin Oncol 2005;23:7159.
Lorigan P, Woll P, O'Brien M, Fosella F, Zildijian S, Welch S, et al
. Phase I trial of BB-10901 (huN901-DM1) given daily by IV infusion for three consecutive days every three weeks in patients with SCLC and other CD56-positive solid tumors. Eur J Cancer 2006;4:195-6.
Whiteman KR, Murphy MF, Cohane KP, Sun W, Carrigan CN, Mayo MF, et al
. Preclinical evaluation of IMGN901 (huN901-DM1) as a potential therapeutic for ovarian cancer. Proc Am Assoc Cancer Res 2008;49. [Abstr. 2135].
Whiteman KR, Johnson HA, Xu S, Pinkas J, Lutz RJ. Lorvotuzumab mertansine (IMGN901) in combination with standard-of-care paclitaxel/carboplatin therapy is highly active in a preclinical xenograft model of ovarian cancer. Proc Am Assoc Cancer Res 2011;52. [Abstr. 1781].
Woll PJ, O'Brien M, Fossella F, Shah M, Clinch Y, O'Keeffe J, et al
. Phase I study of lorvotuzumab mertansine (IMGN901) in patients with CD56-positive solid tumors. Ann Oncol 2010;21 Suppl 8. [Abstr. 536P].
Chanan-Khan A, Wolf J, Garcia J, Gharibo M, Jagannath S, Manfredi D, et al
. Efficacy analysis from a phase I study of lorvotuzumab mertansine (IMGN901) used as monotherapy in patients with heavily pre-treated CD56-positive multiple myeloma. Blood 2010;116:819. [Abstr. 1962].
McCann J, Fossella FV, Villalona-Calero MA, Tolcher AW, Fidias P, Raju R, et al
. Phase II trial of huN901-DM1 in patients with relapsed small cell lung cancer (SCLC) and CD56-positive small cell carcinoma. J Clin Oncol 2007;25 Suppl 18. [Abstr. 18084].
Berdeja JG, Ailawadhi MD, Niesvizky R, Wolf JL, Zildjian SH, O'Leary J, et al
. Phase I study of lorvotuzumab mertansine (IMGN901) in combination with lenalidomide and dexamethasone in patients with CD56-positive relapsed or relapsed/refractory multiple myeloma – A preliminary safety and efficacy analysis of the combination. Blood 2010;116. [Abstr. 1934].
Spigel DR, Bendell J, Mita AC, Argiris A, Kurkjian C, Hann CL, et al
. Phase I/II study to assess the safety, pharmacokinetics (PK) and efficacy of lorvotuzumab mertansine (LM, IMGN901) in combination with carboplatin/etoposide in patients with solid tumors including small-cell lung cancer (SCLC). 37th
ESMO Congress, Vienna. Ann Oncol 2012;23 Suppl 9. [Abstr. 1543TiP].
[Figure 1], [Figure 2]
[Table 1], [Table 2]