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 Table of Contents  
BRIEF REPORT
Year : 2020  |  Volume : 11  |  Issue : 3  |  Page : 153-156

Conserved pathways of apoptosis in leukemia: A short communication


Indepeandent Researcher, Patna, Bihar, India

Date of Submission01-May-2020
Date of Decision05-Jun-2020
Date of Acceptance01-Aug-2020
Date of Web Publication16-Sep-2020

Correspondence Address:
Pushpam Kumar Sinha
101, Vijayshree Complex, Kankarbagh, Patna - 800 020, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_57_20

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  Abstract 

The stem cell nature of leukemia and several other cancers has long been known now. Given that the leukemic blast cells (the large population of aberrantly differentiated blood cancer cells) arise from a rare and quiet population of stem cells called leukemic stem cells (LSCs) which have accumulated multiple mutations in multiple steps spread over the years, the particular hypothesis that cancer results from the loss-of-function mutation in apoptotic gene of the apoptotic pathway would mean that the LSCs and the leukemic blast cells do not undergo apoptosis at all. However, this is not the case; in reality, there are experimental and/or clinical studies showing that the LSCs and the leukemic blast cells do undergo apoptosis in a fully grown cancer, though its rate is less than the proliferation rate. I hypothesize in this article that this apoptosis by itself is significant and its importance cannot be ruled out, though it may not be significant when compared with the apoptosis of blood cells in a healthy person. This means that though leukemia arises through multiple mutations which may include mutations in apoptotic genes too, there are left some conserved pathways of apoptosis in fully grown cancer. A few of these possible conserved pathways of apoptosis in a fully developed leukemia, that I list here, include P53, pro-apoptotic Bcl-2 family members, microRNA, and short interfering RNA.

Keywords: Anti-apoptotic, gene silencing, leukemic stem cell, pro-apoptotic


How to cite this article:
Sinha PK. Conserved pathways of apoptosis in leukemia: A short communication. J Appl Hematol 2020;11:153-6

How to cite this URL:
Sinha PK. Conserved pathways of apoptosis in leukemia: A short communication. J Appl Hematol [serial online] 2020 [cited 2020 Sep 20];11:153-6. Available from: http://www.jahjournal.org/text.asp?2020/11/3/153/295125


  Introduction Top


Leukemia is an uncontrollably growing population of blood cells with aberrant morphology and aberrant function, called the leukemic blast, different from the morphology and function of healthy and terminally differentiated blood cells. The leukemic blast arises from a rare and relatively quiet population of stem cells called the leukemic stem cells (LSCs).[1] Leukemia can be broadly classified into two types: myeloid leukemia and lymphoid leukemia. Myeloid leukemia is the blood cancer of the myeloid lineage of blood cells (megakaryocyte, thrombocyte, erythrocyte, mast cell, basophil, neutrophil, eosinophil, monocyte, and macrophage), and lymphoid leukemia is the blood cancer of the lymphoid lineage of blood cells (natural killer cell or large granular lymphocyte, T lymphocyte, B lymphocyte, and plasma cell).[1] In this article, I focus on only myeloid leukemia and do not talk of lymphoid leukemia. Hence, unless otherwise stated, the word leukemia in this article will mean only myeloid leukemia. Myeloid leukemia has been shown to have a stem cell basis,[2] like cancers of most other organs too.[3]

The stem cells which give rise to terminally differentiated blood cells of all types are called the hematopoietic stem cells (HSCs) which reside in the bone marrow. The HSC can undergo symmetric cell division to give rise to two identical daughter cells which are exact copies of their mother stem cell – this property of HSC is called self-renewal. The HSC can also undergo asymmetric cell division to give rise to two distinct daughter cells, one of which is an exact copy of the mother stem cell and the other is a partially differentiated progeny called the multipotent progenitor (MPP). The MPP can be of either of the two types, common myeloid progenitor or common lymphoid progenitor, whose differentiation, respectively, gives rise to either the myeloid lineage or the lymphoid lineage of blood cells. This is the hierarchical structure of healthy blood cells with HSC at the top. The LSC of acute myeloid leukemia (AML), AML LSC, and the LSC of chronic myeloid leukemia (CML), CML LSC both have properties similar to that of HSC.[4],[5]

Now, the questions that arise are how LSCs are formed from HSCs and how the LSCs give rise to the leukemic blast. I try to answer both these questions in this paragraph. The answer to the first question is given in the review[6] which claims that LSC actually forms after a sequence of multiple mutations in HSC and/or MPP spanning several years, with the first mutation taking place many years before the LSC actually forms. As long as the multiply mutated HSCs or MPPs, on subsequent differentiation, gives rise to healthy blood cells, cancer does not set in, and they (HSCs and MPPs) undergo further mutations. At a certain stage of mutation, after several mutations had already occurred in the HSCs and/or MPPs, the subsequent differentiation gives rise to aberrant (both in morphology and function) blood cells and we say that cancer has set in. It is at this stage that the multiply mutated HSCs and/or MPPs are called LSCs. The LSCs have features similar to HSCs:[2] they have the capability of self-renewal and they are rare and quiet. The answer to the second question is not known at present, and there is a lot of mystery over it and is an active area of research in oncology; the only thing known is that LSCs initiate and sustain cancer. I have tried to answer the second question by a hypothesis, yet unproven, in my article.[1] However, this hypothesis is not the subject matter of this article, and I refrain from discussing it here.

The hypothesis which is the focus of this article is that an important final step in the genesis of leukemia is the upregulation of cell proliferation and the loss-of-function mutation of apoptotic genes in LSCs.[7] Given the features of LSC, it is clear that if leukemia arises due to the loss-of-function mutation of apoptotic genes, then there should be absolutely no apoptosis of LSCs and leukemic blast cells. However, in reality, this is not so.[8] From the work in the article,[8] I conclude that there is significant apoptosis of leukemic cells (both LSCs and leukemic blast cells) in several different types of blood cancers studied, though its rate is less than the proliferation rate. This prompts me to hypothesize that despite the multiple mutations occurring in several genes in leukemia, it is not necessary that these multiple mutations include the mutations in apoptotic genes, and it is necessary that there are still some conserved mechanisms of apoptosis which are left nonmutated.


  Conserved Pathways of Apoptosis Top


Some of the possible conserved mechanisms of apoptosis in leukemia could be:

  1. P53, the tumor suppressor protein. As the name suggests, P53 causes the suppression of tumors by inducing apoptosis of the cell in response to the apoptotic signal, for example, DNA damage.


  2. Out of 112 of the AML patients studied,[9] only 8 were reported to have the mutation in the P53 gene. Thus, in almost 93% of the AML patients studied, the P53 apoptotic gene was conserved, while approximately 20% of the CML patients showed structural aberrations in the P53 gene and approximately 30% of the CML patients showed mutations in the P53 gene.[10],[11] The P53 gene activation can cause cell cycle arrest also in response to certain cellular stresses. The P53 gene exercises its effect through both its transcriptional activation and transcriptional repression activities.[7] In cells with undamaged DNA, the P53 protein is unstable and hence maintained at low levels, but in cells with damaged DNA, the P53 protein stability is increased and hence maintained at high levels. There are two ways in which the upregulation of the P53 gene is linked to DNA damage: first, the carboxy terminus of P53 protein itself can bind to the damaged DNA, and second, the ataxia–telangiectasia (atm) protein links the DNA damage to the upregulation of P53. In other words, the formation of the P53-damaged DNA-atm complex causes at its downstream the transcriptional activation and/or transcriptional repression of several other genes that lead eventually to cell cycle arrest or apoptosis. The most popular gene whose upstream region the tetramer of P53 binds to and causes its transcriptional activation is the BAX gene. Augmented BAX expression causes apoptosis. The target genes of transcriptional repression by P53 are yet not identified, but the work[12] suggests that P53 may repress genes necessary for cell survival and thereby cause apoptosis:

  3. Pro-apoptotic BCL-2 family members (BAX, BAK, and BAD proteins). BCL-2 is a family of proteins which can be classified into the anti-apoptotic proteins (BCL-2, BCL-, BCL-w, MCL-1, and A1) and the pro-apoptotic proteins (BAX, BAK, and BAD).[7] The overexpression of pro-apoptotic BCL-2 family members causes cell death by apoptosis, and the overexpression of anti-apoptotic BCL-2 family members inhibits apoptosis. Navitoclax (ABT-263), ABT-737, and ABT-199 are the popular anticancer drugs being tested in the treatment for leukemia.[13] All the three are antagonists of anti-apoptotic BCL-2 family members. They mimic BH3 domain in their structures similar to the BH3 domain of some or a particular pro-apoptotic BCL-2 family member. It is notable that the anti-apoptotic BCL-2 family member has a BH3 domain-binding site to which the pro-apoptotic BCL-2 family member binds. ABT-263 efficiently binds to BCL-2, BCL-XL and BCL-w, thereby releasing the pro-apoptotic protein to directly target the mitochondrial membrane and cause apoptosis, but because it (ABT-263) has affinity for BCL-XL, the treatment of leukemia with ABT-263 leads to dose-limiting thrombocytopenia.[13] It is notable that platelets are dependent on BCL-XL for their survival. This prompted the research on ABT-199 which has affinity for BCL-2 only and thereby, therefore, does not lead to the destruction of platelets when AML is treated with it (ABT-199). Both ABT-737 and ABT-199 cause cell death in AML cell lines,[13],[14] but the latter is shown to be more potent than the former. The occurrence of cell death in the treatment of leukemic cell lines by ABT-263, ABT-737, and ABT-199, given their modus operandi, clearly demonstrates and hence proves that the apoptotic pathway in control of the pro-apoptotic BCL-2 family proteins is conserved in leukemia
  4. MicroRNAs (miRNAs). As the name suggests, they are short, about 22 nucleotides in length, RNAs, and they are noncoding, normally having the antisense complementarity in the untranslated region (UTR) or the UTR of the gene (thereby called the target gene) from loci unrelated to the miRNA gene.[15] They do not have a direct phenotypic effect on the cell as they do not code any protein. However, they repress the protein levels of their target genes by attacking the respective mRNA of the target gene; they attack mRNA either by cleaving it or by repressing the translation process. If mRNA has sufficient complementarity to miRNA, the miRNA in reduced instruction set computer (RISC) (RNA-induced silencing complex) will specify the cleavage of mRNA; otherwise, if mRNA has a suitable constellation of miRNA complementary sites, the miRNA in RISC will repress translation from the respective mRNA strand.[15] CML is caused by a chromosome translocation that generates the constitutively active Bcr-Abl tyrosine kinase, a fusion protein.[16],[17] Bcr-Abl exercises its malignant effect through uncontrolled proliferation and reduced apoptosis. The anti-apoptotic effect is because of the upregulation of BCL-XL gene through STAT5-dependent pathway, and hence, blockade of the Bcr-Abl kinase activity leads to the reduced expression of BCL-XL and thereby apoptosis.[16] A number of miRNAs regulating the expression of proliferation, apoptosis, or differentiation genes have been found to be upregulated or downregulated in CML. miR-23a, miR-30a, miR-30e, miR-203, miR-320, and miR-424 are known to bind to the Bcr-Abl mRNA and thereby repress its (Bcr-Abl protein) expression.[18] Specifically, I talk of miR-424 here. In Hershkovitz-Rokah et al.'s study,[17] the researchers found that miR-424 expression levels were low in CML cell lines; however, in CML human patients, around 50% of them had elevated levels of miR-424. Although this elevated level was higher than that found in the healthy blood pool, it was not enough to lead to a favorable prognosis of the disease; the researchers needed to overexpress miR-424 many folds (>100-fold compared to the negative controls) to observe its curative effect. Hence, we may safely conjecture, without actual proof, that the apoptotic pathway governed by miR-424 in CML-affected cells may be conserved in some of the patients. At present, not much is known about the regulatory control over miRNA expression. The focus of future research in hematologic oncology should be on finding this regulatory control. Once known, we can answer with definiteness whether a particular miRNA apoptotic pathway will be conserved or not through the evolutionary stages of mutations leading to cancer. The downstream target genes of miRNAs in AML are unclear and hence the role of miRNAs in apoptosis of AML cells is also unclear; especially, we know many miRNAs which have favorable prognosis in AML, but we do not know how. In light of the lack of this knowledge, I refrain from making any claim regarding the conservation of miRNA-governed apoptotic pathway in AML through the evolutionary process of leukemogenesis
  5. Short interfering RNAs (siRNAs). As the name suggests, they are short, about 20–25 base pairs in length RNAs, and they participate in the RNA interference (RNAi) pathway. Unlike miRNA, they are double-stranded, but like miRNA, they are noncoding. Like miRNAs, they cause repression of the target gene expression by either the pretranscriptional gene silencing or the posttranscriptional gene silencing, with the aid of the enzymatic complex. This pathway is known as the RNAi pathway. Although different in structures, both miRNA and siRNA cause the same effect through almost similar pathways. Although the apoptotic role of specific siRNAs in AML and/or CML is known through various literatures,[19],[20],[21] from the data given in these literatures, it is not possible to conclude whether these respective siRNAs may be conserved or not in full-blown cancer.



  Conclusions Top


These are some of the most prominent apoptotic pathways in leukemia; there may be many more dealt with in literature, and many more yet undiscovered. The idea behind this exercise/short communication is that the leukemic patients may be tested for the possible conserved apoptotic pathway post onset of cancer and then thereafter treated by over-activation of that pathway in the leukemic cells.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Pushpam KS. The common genesis of all cancers. J Carcinog Mutagen 2019;10:342.  Back to cited text no. 1
    
2.
Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004;1:80-97.  Back to cited text no. 2
    
3.
Dhawan P, Ahmad R, Srivastava AS, Singh AB. Cancer stem cells and colorectal cancer: An overview. Curr Top Med Chem 2011;11:1592-8.  Back to cited text no. 3
    
4.
Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017;129:1577-85.  Back to cited text no. 4
    
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Zhou H, Xu R. Leukemia stem cells: The root of chronic myeloid leukemia. Protein Cell 2015;6:403-12.  Back to cited text no. 5
    
6.
Corces-Zimmerman MR, Majeti R. Pre-leukemic evolution of hematopoietic stem cells: The importance of early mutations in leukemogenesis. Leukemia 2014;28:2276-82.  Back to cited text no. 6
    
7.
Wickremasinghe RG, Hoffbrand AV. Biochemical and genetic control of apoptosis: Relevance to normal hematopoiesis and hematological malignancies. Blood 1999;93:3587-600.  Back to cited text no. 7
    
8.
Lin CW, Manshouri T, Jilani I, Neuberg D, Patel K, Kantarjian H, et al. Proliferation and apoptosis in acute and chronic leukemias and myelodysplastic syndrome. Leuk Res 2002;26:551-9.  Back to cited text no. 8
    
9.
Fenaux P, Preudhomme C, Quiquandon I, Jonveaux P, Laï JL, Vanrumbeke M, et al. Mutations of the P53 gene in acute myeloid leukaemia. Br J Haematol 1992;80:178-83.  Back to cited text no. 9
    
10.
Mashal R, Shtalrid M, Talpaz M, Kantarjian H, Smith L, Beran M, et al. Rearrangement and expression of p53 in the chronic phase and blast crisis of chronic myelogenous leukemia. Blood 1990;75:180-9.  Back to cited text no. 10
    
11.
Ahuja H, Bar-Eli M, Arlin Z, Advani S, Allen SL, Goldman J, et al. The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia. J Clin Invest 1991;87:2042-7.  Back to cited text no. 11
    
12.
Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 1994;370:220-3.  Back to cited text no. 12
    
13.
Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 2014;4:362-75.  Back to cited text no. 13
    
14.
Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006;10:375-88.  Back to cited text no. 14
    
15.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.  Back to cited text no. 15
    
16.
Horita M, Andreau EJ, Benito A, Arbona C, Sanz C, Benet I, et al. Blockade of the bcr-abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of BCL-XL, J Exp Med 2000;191:977-84.  Back to cited text no. 16
    
17.
Hershkovitz-Rokah O, Modai S, Pasmanic-Chor M, Toren A, Shomron N, Raanani P, et al. Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment. Cancer Lett 2015;360:245-56.  Back to cited text no. 17
    
18.
Yeh CH, Moles R, Nicot C. Clinical significance of microRNAs in chronic and acute human leukemia. Mol Cancer 2016;15:37.  Back to cited text no. 18
    
19.
Karami H, Baradaran B, Esfahani A, Sakhinia M, Sakhinia E. Therapeutic effects of myeloid cell leukemia-1 siRNA on human acute myeloid leukemia cells. Adv Pharm Bull 2014;4:243-8.  Back to cited text no. 19
    
20.
Ptasznik A, Nakata Y, Kalota A, Emerson SG, Gewirtz AM. Short interfering RNA (siRNA) targeting the lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells. Nat Med 2004;10:1187-9.  Back to cited text no. 20
    
21.
Peng Z, Xiao Z, Wang Y, Liu P, Cai Y, Lu S, et al. Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells. Cancer Gene Ther 2004;11:707-12.  Back to cited text no. 21
    




 

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