|Year : 2018 | Volume
| Issue : 2 | Page : 51-58
Cytogenetic analysis of acute myeloid leukemia with t(8;21): Its clinical correlation with loss of X Chromosome and Del (9q)
Afaf Abd El Aziz Abd El Ghafar, Yasmin Nabil El-Sakhawy, Nesma Ahmed Safwat, Heba Mohamed Ismail
Department Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Web Publication||18-Jun-2018|
Dr. Nesma Ahmed Safwat
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo
Source of Support: None, Conflict of Interest: None
BACKGROUND: Translocation (8;21), t(8;21), is one of the most common cytogenetic abnormalities in adult de novo acute myeloid leukemia (AML) patients. It is usually associated with secondary chromosomal abnormalities; however, it's unclear whether these abnormalities affect the clinical characteristics of t(8;21) patients.
OBJECTIVES: To investigate the effect of additional aberrations; loss of X chromosome and deletion of the long arm of chromosome 9 (del 9q)on the clinicopathological and immunophenotypic characteristics and prognostic behavioral of t(8;21) de novo AML.
METHODS: Fifty six adults with de novo AML-M2 were enrolled. Detection of loss of X-chromosome and del 9q were performed using fluorescent in situ hybridization (FISH).
RESULTS: More than half of the patients (53.6%) harbored a secondary chromosomal abnormality in addition to t(8;21). Del 9q was found in 17.9% of the patients. A significant association was found between this chromosomal aberration and age, hepatomegally, high total leucocytic count and low platelets count (P< 0.05). Most patients had poor clinical outcome, high tendency for resistance to therapy and significantly shorter survival. On the other hand, loss of X chromosome was found in 25% of the studied patients and was not related to clinicopathological features or prognostic markers except for high platelets count and low expression of aberrant CD19 (P< 0.05).
CONCLUSIONS: 9q deletion associated t(8;21) could be considered as an adverse prognostic predictor being associated with poor disease outcome and shorter survival of the patients. Thereafter the use of these cytogenetic aberrations would be recommended to guide therapeutic regimens.
Keywords: Acute myeloid leukemia, del 9q, loss of X chromosome, t(8;21)
|How to cite this article:|
Abd El Ghafar AA, El-Sakhawy YN, Safwat NA, Ismail HM. Cytogenetic analysis of acute myeloid leukemia with t(8;21): Its clinical correlation with loss of X Chromosome and Del (9q). J Appl Hematol 2018;9:51-8
|How to cite this URL:|
Abd El Ghafar AA, El-Sakhawy YN, Safwat NA, Ismail HM. Cytogenetic analysis of acute myeloid leukemia with t(8;21): Its clinical correlation with loss of X Chromosome and Del (9q). J Appl Hematol [serial online] 2018 [cited 2018 Jul 22];9:51-8. Available from: http://www.jahjournal.org/text.asp?2018/9/2/51/234555
| Introduction|| |
Translocation (8;21), t(8;21), is among the most frequent recurrent chromosome aberrations in adult de novo acute myeloid leukemia (AML). At the molecular level, t(8;21) results in the formation of the fusion gene AML1-ETO (also named RUNX1-RUNX1T) that alters the individual components of the heterodimeric core binding factor transcription complex, a master regulator of definitive hematopoiesis.
This fusion protein impairs the normal transcriptional activity of RUNX1, leading to enhanced self-renewal of hematopoietic progenitors, and altered epigenetic environment of stem cells, without causing acute leukemia. AML1-ETO creates the ideal condition for leukemia development promoting secondary mutagenic events. Alternatively, deregulated splicing of AML1-ETO transcripts may produce several splice sites such as AML1-ETO9a. This variant may contribute to the speed of transformation results in the earlier onset of leukemia or may even cooperate with AML1-ETO being itself a secondary event in leukemogenesis.
The nature of additional leukemogenic events in t(8;21) patients is evidenced by additional cytogenetic or molecular genetic abnormalities. The two most common recurrent cytogenetic abnormalities associated with t(8;21) are loss of a sex chromosome and deletion of the long arm of chromosome 9 (del 9q). However, their impact on survival is controversial. Other abnormalities include trisomy 4 and 8 and tetraploid or near-tetraploid clones.
In addition to cytogenetic abnormalities, mutations of growth factor receptors, proto-oncogenes, and transcription factors are also identified in t (8,21) AML, which include stem-cell factor (c-KIT) and FMS-related tyrosine kinase 3 (FLT3). KIT mutations, as the potential molecular markers, are found in 12%–46% of t (8,21). The prognostic impact of KIT mutations has been investigated in several studies.
The t(8; 21) AML represents a favorable cytogenetic AML subgroup based on its excellent responsiveness to induction chemotherapy and high complete remission (CR) rate. However, although the overall disease-free survival reaches about 60% in t (8;21) AML, about 30%–40% of cases relapse after standard intensive chemotherapy, of which half become treatment resistant. Therefore, t(8;21) AML is a heterogeneous disease with poor survival in a subset of patients. Multiple risk factors, including the white blood cell (WBC) count at initial examination, blood platelet count, sex chromosome abnormality, and percentage of peripheral blood (PB) blasts, have been reported as prognostic factors in t(8;21) AML.
To highlight the role of the secondary cytogenetic abnormalities that accompany t(8;21), the aim of this study was to investigate the effect of additional aberrations (loss of X chromosome and del [9q]) on the clinicopathological and prognostic behavior of t(8;21) de novo AML patients.
| Materials and Methods|| |
This prospective study was carried out on 56 newly diagnosed adults with AML-M2 recruited from Hematology and Oncology Unit at Ain Shams University hospital. Their ages ranged from 19 to 61 years (mean 33.1 ± 12.5 years). Thirty-two were male and 24 were female with male-to-female ratio of 1.3:1. An informed consent was obtained from each patient before participation in the study. The procedures applied in this study were approved by the Ethical Committee of Human Experimentation of Ain Shams University, and are in accordance with the Helsinki Declaration of 1975.
Patients were diagnosed on the basis of (i) complete history taking and through clinical examination; ii) laboratory investigations including complete blood count using LH 750 (Beckman Coulter), examination of Leishman-stained PB films, bone marrow (BM) aspiration, and examination; and cytochemical studies using myeloperoxidase stain together with flow cytometric immunophenotyping using EPICS XL Coulter flow cytometer. Fluorescent in situ hybridization (FISH analysis using locus-specific identifier dual fusion (LSC DF) for the detection of t(8;21) and centromeric enumeration probe (CEP) for loss of X chromosome as well as locus-specific identifier Abelson (LSI ABL) probe for del (9q). Two age-matched healthy volunteers were used as controls; to check the intensity of signals of the used probes.
PB and BM samples were collected on ethylenediaminetetraacetic acid (1.2 mg/ml) for morphological and immunophenotyping. BM aspirates were collected in sterile preservative-free lithium heparin-coated vacutainer tubes for cytogenetic analysis.
Fluorescent in situ hybridization technique
The FISH analysis was performed on BM aspirates using locus-specific identifier dual fusion (LSI DF) for the detection of t(8;21) CEP for loss of X chromosome as well as (LSI ABL) probe for del 9q. At least 100 interphase nuclei and/or 20 metaphases were scanned under fluorescence microscope for the detection of t(8;21), loss of X chromosome, and del 9q. The t(8;21) was reported if two yellow signals, one red and one green were detected in >1.3% of cells. Loss of X chromosome was reported if one red signal was noticed in >10% of cells in female patients and if one green signal was noticed in >10% of cells in male patients. Heterozygous del (9q) was noticed if one aqua signal is reported in >10% of cells and homozygous del 9q was represented by the absence of aqua signal in >10% of cells.
Induction therapy with cytarabine and an anthracycline remains a standard of care in AML. The standard combination is the 7 + 3 protocol, with a 7 days continuous infusion of cytarabine at the dosage of 100 or 200 mg/m 2/day on days 1–7 and daunorubicin at 60 mg/m 2/day on days 1–3. Induction was considered successful if CR was achieved (CR; BM blasts <5%). Further postremission therapy was given in the form of 3–4 cycles of HiDAC (High-dose Ara-C) followed by allogeneic hematopoietic stem cell transplantation from human leukocyte antigen -matched donor. If CR was not achieved (BM blasts >5%), reinduction with three and seven protocols was adopted.
The follow-up strategy that was used to assess remission included blood counts monthly, and BM aspirates performed for every 3 months. Patients were followed up for a median of 16 (range 6–24). Response to therapy was assessed at the end of induction, and CR was considered when the BM examination was normal with <5% blasts and no Auer rods More Details, recovery of absolute neutrophil count >1000/μL, and platelets >100,000/μL, and extramedullary disease has resolved and disappearance of the cytogenetic markers. Relapse was defined as the reappearance of leukemic cells in the BM (≥5%) or in the PB or as the appearance of a new extramedullary site of disease in patients with a previously documented CR.
Disease outcome was evaluated according to the standard prognostic factors such as age, gender, WBC count, platelet counts, and hepatosplenomegaly  in addition to relapse and disease-related death of the studied patients.
Overall survival ( OS) was measured from the date of diagnosis until the date of death or last date is known to be alive while disease-free survival (DFS) was measured from the date of CR until the date of death or relapse censoring patients at last follow-up if alive.
Data were collected, revised, coded, and entered into the Statistical Package for Social Science (IBM SPSS™) version 20 (SPSS 20, IBM, Armonk, NY, United States of America). Qualitative data were presented as numbers and percentages while quantitative data were entered into the Kolmogrov–Smirnov test of normality and parametric distribution data were presented as mean, standard deviations, and ranges while nonparametric distribution data were presented as a median with interquartile range. To compare parametric quantitative variables between two groups, Student's t-test was applied. For comparison of nonparametric quantitative variables between two groups, Mann–Whitney test was used. The comparison between two groups with qualitative data was done using Chi-squared test and/or Fisher's exact test instead of Chi-square when the expected count in any cell found <5.
Survival analysis was estimated using the Kaplan − Meier method and compared by the log-rank test. Results that reached a level of P < 0.05 were considered statistically significant. Logistic regression analysis was employed to determine variables affecting death and relapse.
| Results|| |
All the studied patients were positive for t(8;21) as it was one of the study's inclusion criteria. Of the 56 patients, 32 (57.1%) had t(8;21) alone, 14 patients (25%) had loss of X chromosome, and 10 patients (17.9%) were positive for del of 9q. The clinical and laboratory data of all the studied patients with AML are shown in [Table 1].
|Table 1: Demographic, clinical and laboratory data of all the studied acute myeloid leukemia with t(8;21) patients|
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Clinical and laboratory characteristics of acute myeloid leukemia patients in relation del 9q and to loss of X chromosome
In the current study, del 9q was significantly associated with multiple parameters such as age (P = 0.036), hepatomegaly (P = 0.029), total leukocytic count (TLC) (P = 0.015), and platelet counts (P = 0.016) [Table 2].
|Table 2: Clinical and laboratory characteristics of acute myeloid leukemia patients t(8;21) in relation to deletion of the long arm of chromosome 9|
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As regards the loss of X chromosome, there was only a significant association with platelets count (P = 0.044) and aberrant expression of CD19 on the myeloblasts (P = 0.046) among AML patients with loss of X chromosome. However, all the other studied parameters were statistically nonsignificant [Table 3].
|Table 3: Clinical and laboratory characteristics in relation to loss of X chromosome among acute myeloid leukemia with t (8;21) patients|
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Prognostic impact of the studied chromosomal aberrations in acute myeloid leukemia patients
AML patients with del 9q had poor disease outcome (P = 0.023) as shown by their poor response to therapy and high incidence of relapse [Table 2]. Similar results were observed when patients with and without del 9q were compared after removing patients with loss of X chromosome from the analysis.
The estimated 2-year OS rate in del 9 positive patients was 10 ± 1.414 months compared to 22.447 ± 1.057 months in negative cases (Log Rank 9.181, P = 0.002) and DFS rate was 9.5 ± 1.5 versus 20.363 ± 1.193, respectively (Log Rank 7.104, P = 0.008) [Table 4] and [Figure 1].
|Table 4: Overall and disease-free survival of the studied acute myeloid leukemia patients|
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|Figure 1: Overall and disease-free survival of acute myeloid leukemia with t(8;21) patients in relation to del 9q|
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Logistic regression analysis showed that del 9q was a significant independent factor for death among the studied patients (OR = 8.7, 95%CI = 1.4–52.7, P = 0.018). Moreover, it was also an independent factor affecting relapse (OR = 5.3,95%CI = 1.3–32.9, P = 0.04).
On the other hand, most of the patients with loss of X chromosome tended to have good course of the disease as they attained CR without relapse and were alive. However, these findings could not reach the statistical significance level [Table 3]. The same results were obtained when patients with and without loss of X chromosome were compared after removing patients with del 9q from the analysis.
Patients with loss of X chromosome had a DFS 17.6 ± 2.1 months % versus 19.3 ± 1.4% in negative cases (P = 0.837) and an estimated 2-year OS was 18.6 ± 2.2 months compared to 20.9 ± 1.4, respectively (P = 0.886) [Table 4].
| Discussion|| |
The t(8;21)(q22;q22) is one of the most common cytogenetic abnormalities in adult de novo AML patients. For almost three decades, standard cytogenetic analysis at diagnosis has been a part of the initial workup for AML, and karyotypic aberrations have been considered the most important predictor for outcome.
The t(8;21) generates a novel fusion protein, AML1-ETO which affects a wide range of cellular molecules; first, gene expression as well as ribosomal function are affected. Second, it can reduce DNA repair mechanisms. Thus, AML1-ETO may alter the epigenetic environment of stem cells and drive an ideal condition for leukemia development, promoting secondary mutagenic events. Third, the responses to hematopoietic growth factors are altered due to altered cytokine release, receptor expression, and downstream intracellular signaling. Finally, the regulation of apoptosis is altered, and the cells show the activation of stress responses. Most of these alterations are in favor of increased proliferation and survival and decreased differentiation, but the fusion protein also has opposite effects, and this may explain why the fusion protein alone cannot induce leukemic transformation.
More challenging will be to identify the molecular mechanisms of additional cytogenetic defects, such as loss or gain of specific chromosomes associated with t(8,21) AML, because losses and gains suggest the presence of possibly one or more tumor suppressors or amplified oncogenes.
The most frequent cytogenetic aberrations are loss of sex chromosome followed by del 9q and trisomy 8. However, previous studies showed conflicting data regarding the role of secondary cytogenetic aberrations in addition to t(8;21).
The current study revealed that around half of the studied patients (42.9%) harbored a secondary chromosomal abnormality in addition to t(8;21). The most frequent one was loss of X chromosome (25%) followed by del (9q) (17.9%) of the patients. In a preliminary study, Marcucci et al. noticed the loss of X chromosome in 32.8% of the t(8;21) patients and del 9q was found in 17.4% of patients. Besides, Appelbaum et al. found the loss of X chromosome and del 9q in 16% and14% of the patients, respectively. Whereas, Krauth et al. detected a higher incidence of loss of X chromosome (46.8%) while del 9q was found in 15.1% of the studied patients. This difference may be attributed to difference in sample size, characteristics of the studied population, and the geographic distribution of the patients enrolled in the studies.
In a previous review article, Peterson et al. analyzed the frequency of loss of X chromosome and del(9q) in t(8,21) AML patients reported by different studies and showed that 35% of female t(8,21) patients were missing one X chromosome and del(9q) was detected in 18% of the patients.,
In the present study, the studied t (8;21) patients were mostly young and presented with mild leukocytosis, moderate anemia, mild thrombocytopenia, low blast percentages, and no hepatosplenomegaly. They also had a favorable course of the disease as they attained CR at the induction phase and the majority remained alive with no relapsed disease until the end of follow-up. These results were in agreement with Prebet et al. who stated that-t(8;21) AML represents a favorable cytogenetic AML subgroup based on its excellent responsiveness to induction chemotherapy, high CR rate, a reduced relapse risk, and an increased overall survival.
On the contrary, Gao et al. found that 30% to 40% of t(8;21) AML cases relapse after standard intensive chemotherapy and half of which become treatment resistant. Appelbaum et al. justified the poor prognosis in these patients by the presence of multiple poor prognostic factors such as old age, WBC count at initial examination, blood platelet count, blast percentage, extramedullary disease, and chromosomal abnormalities.
Our results showed that most of the studied patients with t(8;21) together with del 9q had inferior disease outcome as they were irresponsive to therapy and had a higher incidence of relapse and/or death. They also had short DFS and OS. Furthermore, our work reported that del 9q was independent factor for both death and relapse. This was in agreement with the study done by Jourdan et al. who found that patients with t (8;21) and del 9q had a refractory clinical course of the disease together with short DFS and inferior OS. The negative effect of del 9q on the disease prognosis could also occur as a result of loss the tumor suppressor genes such as TLE 1 and TLE 4 that are located on the long arm of chromosome 9. The knockdown of these genes lead to increased cell division and a significant decrease in apoptosis.
In this study, the del 9q poor prognostic disease could also be attributed to its significant association with several adverse prognostic markers such as old age, hepatomegaly, and high WBC or platelet counts. Elderly patients are intrinsically resistant to chemotherapy due to the comorbidities and the poor reserve of the stem cells in the BM. Therefore, they do not tolerate myelosuppressive chemotherapy and there is high treatment-related mortality. Besides, very high WBC counts are associated with an increased risk of tumor lysis syndrome and leukostasis that lead to poor disease prognosis.
On the other hand, Marcucci et al. noticed that del 9q with t(8;21) did not influence the disease outcome, DFS nor the OS of the studied patients. Moroever, Peniket et al. noted that patients with del 9 had a strikingly good response to chemotherapy and all of the studied patients attained CR. Lin et al. found that the patients with del 9q in addition to t(8;21) had longer event-free survival than those with sole t(8; 21). Therefore, they considered del 9q as a favorable prognostic disease marker.
The different results of the impact of del 9q on the clinical course of the disease raises the suspicion about the molecular markers that may play a vital role in the disease outcome. The favorable prognosis of del 9q was attributed to its association with CEBPA mutations that confer good prognosis. The CEBPA transcription factor is involved in cell cycle arrest, repression of self-renewal, and myeloid differentiation during normal hematopoiesis. In AML, mutations in CEBPA result in a cellular differentiation block. However, RUNX1–RUNX1T1 in t(8;21) blocks CEBPA-dependent activation of its own promoter and thereby inhibits autoregulation and its blocking effect.
As regards the presence of t(8;21) together with the loss of X chromosome, we could not find a statistical association between the loss of X chromosome and disease outcome or different prognostic clinicopathological parameters except for the aberrant expression of CD19 on the myeloblasts. This was in agreement with Lin et al. and Hsiao et al. who found that the loss of X chromosome had no impact on the disease outcome and prognosis as it did not significantly affect the rate of occurrence of CR in the studied patients. Their studies as well as ours were limited by the small sample size that rendered the comparison difficult with other studies.
Interestingly, most patients with loss of X chromosome tended to have a good course of the disease as they attained CR without relapse or death. This may be attributed to its association with multiple favorable prognostic factors. Loss of X chromosome was associated with young age, high hemoglobin level, and platelet count, low WBC count together with low percentage of PB and BM blasts. However, these findings could not reach a statistically significant level. This was in accordance with the study done by Krauth et al. which revealed that the loss of X chromosome was a favorable prognostic marker and was associated with long DFS.
On the contrary, Chen et al. noted that the patients with t(8;21) and loss of X chromosome had a trend toward inferior DFS and OS; although, this was not statistically significant. This may be attributed to loss of the tumor suppressor genes located in the pseudoautosomal region on the X chromosome. One of these genes is CSF2RA gene coding for granulocyte macrophage colony-stimulating factor (GM-CSF) that plays a vital role in the control of the proliferation, survival, and differentiation of the myeloid. Therefore, loss of X chromosome leading to downregulation of GM-CSF signaling is a contributing factor to t (8;21)-induced leukemia.
| Conclusion|| |
This study highlighted the importance of secondary chromosomal abnormalities that associated t(8;21) and could only predict the poor prognostic impact of the del 9q on the clinical course of the disease and the OS of the patients. These patients with poor-risk cytogenetics are expected to have poor outcomes with chemotherapy alone; hence, they are suitable candidates for hematopoietic stem cell transplantation. Further studies on a larger number of patients with prolonged follow-up periods for more comprehensive statistical analysis and better conclusions for the impact of secondary chromosomal abnormalities on the clinical course of the disease in patients with t(8;21) AML.
Investigating other mutations associated with t(8,21) such as c-kit would provide additional value and refine the risk stratification of patients at diagnosis and to optimize their treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]