|Year : 2019 | Volume
| Issue : 2 | Page : 141-148
Clinicopathological significance of common genetic alterations in patients with acute myeloid leukaemia 1-eight twenty-one of acute myeloid leukaemia: a retrospective cohort study
Sukanta Nath1, Jina Bhattacharyya2, Manash P Barman3, Dushyant Kumar1, Renu Saxena4, Sudha Sazawal4, Kandarpa K Saikia PhD 1
1 Department of Bioengineering and Technology, Gauhati University, Guwahati, India
2 Department of Clinical Haematology, Gauhati Medical College and Hospital, Guwahati, India
3 Department of Statistics, Dibrugarh University, Dibrugarh, India
4 Department of Haematology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||21-May-2019|
|Date of Acceptance||21-Aug-2019|
|Date of Web Publication||15-Nov-2019|
Kandarpa K Saikia
Associate Professor and Head, Department of Bioengineering and Technology Gauhati University, Guwahati 781014, Assam
Source of Support: None, Conflict of Interest: None
Objectives Acute myeloid leukaemia 1-eight twenty-one (AML1-ETO) is the most frequent abnormality seen in ∼40% of patients with acute myeloid leukaemia with French-American-British-M2 morphology and has received much attention over the past decade. We performed this study to investigate the prevalence and clinical significance of AML1-ETO in a cohort in Assam, India. Coprevalence and clinical significance of FMS-like tyrosine kinase 3, nucleophosmin 1 (NPM1), and p53 mutations, expression of epidermal growth factor receptor (EGFR), and flow markers were also documented and co-related with disease progress.
Materials and methods Peripheral blood/bone marrow aspirates were collected from 165 de novo acute myeloid leukaemia patients. Reverse transcriptase PCR and real-time PCR assays were used for detection. Statistical analyses were carried out using statistical packages SPSS 22.0 and Epi Info 2000.
Results AML1-ETO t(8;21)(q22;q22) were detected in 24 of 165 (14.60%, 95% confidence interval: 9.77–20.56) samples. The morphologic finding of bone marrow in AML1-ETO-positive patients revealed a higher occurrence of Auer rods. Prominent golgi and abnormal granules were abundantly found with an increasing number of large blasts. The prevalence of NPM1, p53 and EGFR were detected in 7/24 (29.50%), 2/24 (10.50%), and 4/24 (17%) patients, respectively. There was no significant difference in the overall survival (P=0.68) between AML1-ETO-positive and AML1-ETO-negative patients. White blood cell (WBC) count (P=0.00), platelet count (P=0.00), haemoglobin level (P=0.03) and blast count (P=0.01) showed a significant difference between AML1-ETO alive and dead patients. NPM1 mutation was associated with a high WBC count. Association of EGFR and NPM1 in AML-ETO-positive patients was not significant (P=0.75 and 0.88, respectively) compared with AML1-ETO-negative patients.
Conclusion In this cohort study, the remission rate of AML1-ETO t(8;21) was not as high as compared with western countries. The presence of NPM1 mutants in AML1-ETO patents is a striking observation, but NPM1 and EGFR had no significant impact on AML1-ETO patients.
Keywords: acute myeloid leukaemia, acute myeloid leukaemia 1-eight twenty-one, coprevalence, genetic alteration, prognosis
|How to cite this article:|
Nath S, Bhattacharyya J, Barman MP, Kumar D, Saxena R, Sazawal S, Saikia KK. Clinicopathological significance of common genetic alterations in patients with acute myeloid leukaemia 1-eight twenty-one of acute myeloid leukaemia: a retrospective cohort study. Egypt J Haematol 2019;44:141-8
|How to cite this URL:|
Nath S, Bhattacharyya J, Barman MP, Kumar D, Saxena R, Sazawal S, Saikia KK. Clinicopathological significance of common genetic alterations in patients with acute myeloid leukaemia 1-eight twenty-one of acute myeloid leukaemia: a retrospective cohort study. Egypt J Haematol [serial online] 2019 [cited 2019 Dec 5];44:141-8. Available from: http://www.ehj.eg.net/text.asp?2019/44/2/141/271079
| Introduction|| |
Acute myeloid leukaemia (AML) is a clonal hematopoietic disorder resulting from the cooperation of different genetic alterations of different classes. Chromosomal translocations such as t(8;21)(q22;q22), t(16;16)(p13;q22) and t(15;17)(q22;q12∼21) are common in AML with favourable prognosis . The fusion of acute myeloid leukaemia 1, also known as RUNX1 (AML1) and eight twenty-one, also known as RUNX1T1 (ETO) genes results in a hybrid AML1-ETO mRNA, which in turn translates into a chimeric protein . This chimeric protein AML1-ETO, a transcription factor, implicated in both, gene repression and activation , blocks myeloid differentiation . The in-frame fusion of AML1 to ETO generally occurs from break-point in AML1 in intron 5–6 and in ETO in intron 1b-2 . The prevalence of AML1-ETO was reported by a number of studies in different ethnic populations ,,,. In India, the overall incidence of AML1-ETO was reported as 14.58% in adults .
Nucleophosmin 1 (NPM1) and FMS-like tyrosine kinase 3 (FLT3) are two frequently occurring mutations in AML showing favourable and poor prognosis, respectively . An earlier study reported that the tumour suppressor p53 is the most commonly mutated gene in human solid tumours, but genomic inactivation of p53 is much less common in haematological malignancies . High expression of epidermal growth factor receptor (EGFR) in different epithelial cancers is associated with poor outcomes, and, recently, Sun et al.  also reported the same in AML. Immunophenotyping is very important in AML to diagnose and classify its subtypes . The expressions of myeloperoxidase (MPO), CD13, CD34, CD56, and human leukocyte antigen-DR isotype (HLA-DR) are common in t(8;21) leukaemic blasts . AML1-ETO t(8;21) is the hallmark of AML-M2 subtype, which indicates patient stratification on cytarabine treatment, along with daunorubicin. The remission rate in AML1-ETO-positive patients was reported to be more than 80% after successful chemotherapy .
To date, there is a paucity of studies from North East India relating to the clinical significance of other genetic alterations and flow markers in AML1-ETO patients, which prompted us to carry out this study. Here, we investigated the prevalence and prognosis of AML1-ETO along with the association of specific molecular markers, which are mutant FLT3, NPM1, and p53, along with EGFR gene expression and flow markers on AML1-ETO-positive patients, in a cohort of 165 AML patients from North East India.
| Materials and methods|| |
Bone marrow aspirates or peripheral blood samples were collected from 165 consecutive AML patients at diagnosis at the Department of Clinical Haematology, Gauhati Medical College and Hospital. Ethical approval was obtained from the Institutional Ethical Committee of Gauhati University, Guwahati, Assam, India (GUEC-12/2015). To perform this study, from each patient, written informed consent was obtained.
Cytogenetic analysis and immunophenotyping
Cytogenetic analysis was performed by standard techniques following WHO and French-American-British classifications . Karyotyping was performed as per the International System for Human Cytogenetic Nomenclature , and immunophenotyping was performed on the basis of a primary CD45/side scatter (SSC) gating procedure, as previously described .
Isolation of nucleic acids and cDNA synthesis
Genomic DNA and total cellular RNA were isolated from bone marrow or peripheral blood samples (depending upon the white blood cell (WBC) counts) by using HiPurA Blood Genomic DNA Miniprep Purification Kit (HiMedia Laboratories Pvt Ltd, Mumbai, India) and QIAamp RNA blood mini kit (Qiagen GmbH, Hilden, Germany), respectively, following the manufacturer’s protocol. The first strand cDNA synthesis was carried out for qRT-PCR using Superscript III First-Strand Synthesis System (Thermo Fisher Scientific, Waltham, Massachusetts, United States).
qRT-PCR analysis of acute myeloid leukaemia 1-eight twenty-one t(8;21)(q22;q22) translocation and epidermal growth factor receptor gene expression
TaqMan PCR reactions were carried out from cDNA samples using inventoried TaqMan assays from Thermo Fisher Scientific. For detecting AML1-ETO translocation, assay ID: Hs03024873_ft, and, for EGFR expression, assay ID: Hs01076078_m1, were used along with TaqMan Universal Master Mix II with UNG. StepOnePlus Real-Time PCR system (Thermo Fisher Scientific) was used to analyze where glyceraldehyde 3-phosphate dehydrogenase (GAPDH) assay ID: Hs99999905_m1 served as a housekeeping gene.
Expression levels of all AML1-ETO-positive patients were assessed as previously described , except for GAPDH, which was used as endogenous control instead of ABL. All samples were normalized against GAPDH expression to correct for variabilities in RNA quality and cDNA synthesis. Qualitative detection of AML1-ETO was performed by reverse transcriptase PCR by using the primers, as previously described , and, as endogenous control, human GAPDH primers were used, as mentioned before .
Analysis of nucleophosmin 1 and FMS-like tyrosine kinase 3 mutations
NPM1 and FLT3 mutations were detected by using genomic DNA, as previously described ,. FLT3-D835 mutation was detected through a PCR-RFLP method, with the forward primer of 5′-GCCAGGAACGTGCTTGTCACC-3′ and the reverse primer of 5′-CCACAGTGAGTGCAGTTGTTTACC-3′, and restriction digestion with EcoRV, as per the manufacturer’s instructions. Somatic p53 gene mutations in exons 5–9 were studied using polymerase chain reaction single-strand conformation polymorphism and sequencing techniques, as described by Pathak et al. .
The focus of the statistical data analysis in our study was to estimate and determine the frequency and pattern of FLT3 mutation, NPM1 mutation, p53 mutation, EGFR expression, various immunophenotypic markers and their possible clinical relevance in disease progression and survival in relation to age, sex, WBC, platelet count and blast count percentage. Associations between two or more qualitative variables were examined and assessed using Pearson χ2 and Fisher exact tests, as appropriate. Quantitative data such as age, WBC, platelet count, haemoglobin levels and blast count percentage among the two independent groups were analyzed using unpaired ‘t’ and Mann–Whitney U-tests, as appropriate. Overall survival (OS) was calculated using the Kaplan–Meier method to estimate overall and group-wise median survival. To be statistically significant, a two-sided P value less than 0.05 was considered. All statistical analyses were carried out using statistical packages SPSS 22.0 (SPSS Inc., Chicago, Illinois, USA) and Epi Info 2000 (Centers for Disease Control and Prevention, Atlanta, Georgia, USA).
As per standard protocol, all AML1-ETO patients were treated at the Department of Clinical Haematology, in Gauhati Medical College and Hospital, Assam, India. For patients less than 12 years of age, Berlin–Frankfurt–Munster87 protocol was followed, and, for adult patients (<50 years), remission induction therapy ‘7+3 regimen’ of cytarabine (100 mg/m2) for 7 days plus daunorubicin (60 mg/m2) for 3 days was used. Three cycles of high-dose cytarabine 3 g/m2 every 12 h on days 1, 3 and 5 were given as consolidation therapy. For older patients, low-dose chemotherapy regimens were given as per requirement. In addition, fluconazole prophylaxis and antibiotic coverage were given as per the requirement to those patients.
| Results|| |
In our cohort study, 24/165 (14.60%, 95% confidence interval: 9.77–20.56) samples were detected as AML1-ETO t(8;21) positive. Clinical characteristic of AML1-ETO-positive and AML1-ETO-negative patients are summarized in [Table 1]. Comparison between AML1-ETO alive and AML1-ETO dead patients are summarized in [Table 2]. All t(8;21)(q22;q22) cases were cytogenetically confirmed. MPO, CD34, CD13, CD33, CD117 and HLA-DR were detected in most of the AML1-ETO t(8;21) patients ([Table 1]). FLT3 mutation was not detected in AML1-ETO patients. NPM1 mutation was detected in 7/24 (29.20%) and EGFR expression was documented in 4/24 (17%) patients. The expression level of AML1-ETO was n=24, median 32.09, range: 2.19–478.99. PCR analysis revealed that AML1-ETO translocation produced a band of 95 bp, whereas the housekeeping gene GAPGH produced a band of 460 bp ([Figure 1]). Treatment result and monitoring of minimal residual disease (MRD): for assessment of response to therapy and for disease follow-up, MRD plays a very significant role. In AML, AML1-ETO t(8;21)(q22;q22) translocation fusion gene is a molecular marker for monitoring MRD. On day 14 and day 28, bone marrow examinations were performed to detect MRD. Complete remission (CR) was achieved if, within the marrow, less than 5% leukemic blasts’ count was observed and, in peripheral blood, neutrophils more than 1000/µl and platelets more than 100 000/µl were noticed over 4 weeks. qRT-PCR analysis revealed the absence of AML1-ETO fusion transcripts in 14 patients after chemotherapy, whereas seven patients were detected as positive after induction and expired eventually. CR was achieved after induction and consolidation therapy in 14 of 24 (59%) of patients. Because of severe bleeding, three patients died before the induction therapy could be started. [Figure 2] shows the survival analysis between AML1-ETO-positive and negative patients (log-rank P=0.681).
|Table 1 Clinical characteristics of acute myeloid leukaemia 1-eight twenty-one-positive and acute myeloid leukaemia 1-eight twenty-one-negative patients|
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|Table 2 Comparison between acute myeloid leukaemia 1-eight twenty-one alive and acute myeloid leukaemia 1-eight twenty-one dead patients|
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|Figure 1 Detection of AML1-ETO, acute myeloid leukaemia 1-eight twenty-one (AML1/ETO) patients by PCR amplification, 2% agarose gel shows PCR amplified product for AML1/ETO lane 1=50 bp ladder, lane 2=positive control, lane 3 and 4=patient samples, lane 5=normal control, lane 6=no template control, lane7–8=GAPDH of patients.|
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|Figure 2 Survival analysis between acute myeloid leukaemia 1-eight twenty-one (AML1-ETO), AML1-ETO-positive and negative patients (log-rank P=0.681).|
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| Discussion|| |
The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor ETO, is a recurring cytogenetic abnormality in AML and holds a great diagnostic and prognostic value, along with therapeutic implications . The fusion protein AML1/ETO plays a major role in the pathogenesis of t(8;21) AML and is known to be associated with favorable prognosis. Prevalence and prognostic impact of AML1-ETO were assessed in our cohort study consisting of 165 de novo AML patients. The incidence of AML1-ETO transcripts detected in this population was 14.60%, which is in coherence with other studies of Asian and western countries ([Table 3]).
|Table 3 Shows the acute myeloid leukaemia 1-eight twenty-one prevalence in acute myeloid leukaemia in various studies|
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There were no significant differences of sex, age group, WBC counts, platelet count, haemoglobin level and blast count between AML1-ETO-positive and AML1-ETO-negative patients, whereas WBC count, platelet count, haemoglobin level and blast count showed a significant difference between AML1-ETO alive and dead patients. FLT3-ITD mutation is found to be rare in AML1-ETO , and we are completely in agreement with their study, as none of the AML1-ETO patients harbored the FLT3-ITD mutation in this study. The frequency of FLT3-D835 mutation is very low in AML-M2 with AML1-ETO , and there was no evidence of such association in our study. The incidence of NPM1 mutation in AML1-ETO was not evident in several studies ,, but Wang et al.  reported the presence of NPM1 mutation in AML-M2. Chauhan et al.  reported the presence of NPM1 in Indian AML1-ETO patients, although the frequency was lower. High frequency of NPM1 mutation in AML1-ETO might be an indication that NPM1 mutation is abundant in AML-M2 and/or AML1-ETO in the Asian population. Although EGFR leads to poor prognosis in many epithelial cancers, in AML-ETO patients, its role is poorly understood. In this study, there was no significant impact of NPM1 and EGFR in AML1-ETO-positive patients. At diagnosis, high WBC and high blast percentage were associated with poor prognosis in AML1-ETO patients . In this study, WBC count and blast count were significantly higher in dead patients, which could be one of the reasons for the strong adverse effect on their OS. Earlier reports showed that patients with medium platelet count had longer OS and disease-free survival than those with low or high platelet count in AML . In this study, platelet count was significantly lower in dead patients compared with live patients, which could be another underlying cause of death. A previous study reported that the adverse impact of anemia has been documented in patients with lymphomas and leukaemias . In this study, haemoglobin level was significantly lower in dead patients compared with live patients, which could be another cause of lower OS. Other reasons could be an elevated level of c-KIT expression or presence of a c-KIT mutation, which was reported earlier as a poor prognostic indicator in AML1-ETO-positive patients ,, which we could not confirm, as we did not assess the prognostic value of c-KIT in our study group. Another reason could be the persistence of the AML1/ETO fusion transcript in patients who were not treated with allogeneic bone marrow transplantation due to financial constraint. Somatic p53 mutation is already reported to act as an independent poor prognostic factor for OS and disease-free survival among patients with complex karyotype in AML , but, to our knowledge, there is hardly any report on AML1-ETO patients from India. In this study, no p53 mutations were detected from exon 5 to exon 9; however, two patients with AML1-ETO were detected with SNPs in intron 7. Although the OS was poor for those patients, we could not draw any conclusion with regard to the outcome, as the sample size was too small. However, Deng et al.  suggested that SNPs in intron regions generate splice variants of transcripts and promote or disrupt binding and function of long noncoding RNAs.
Flow markers such as CD34 and CD56 were predicted to be adverse prognostic indicators in AML by different studies ,,. In this study, a total of 10/24 (42%) AML1-ETO patients were positive for CD34. Among the 10 patients with poor OS, six patients had CD34. Larger studies are warranted to confirm CD34 as a poor prognosis indicator, as the other four patients in AML1-ETO alive group did not show any adverse effect. The expression of CD7 and CD19 was reported to be linked with poor prognosis in AML ,; however, the same is yet to be confirmed in AML1-ETO-positive patients. Among these 10 patients with lower OS, two patients were detected with CD56 (one patient coexpressed with CD34), two patients with CD7 and two patients with CD19 (one patient coexpressed with CD34) and showed poor prognosis. Any concrete conclusion cannot be made with such a small number of patients. Additional cytogenetic abnormalities and extramedullary manifestations are also reported to be adverse prognostic factors in AML1-ETO-positive patients ,. In this study, one AML1-ETO patient had del(7)(q32) and showed poor prognosis. Although, in western countries, the CR rate in AML1-ETO is a bit higher ,, in our study population, the rate was bit lower, which could be due to ethnic or geographic differences also. Study limitations include no bone marrow transplantation being carried out due to financial constraints, which could affect the OS in AML1-ETO patients. Different studies described the association of genetic alterations between different classes in AML, because expression of the AML1-ETO fusion protein alone is not sufficient to induce leukaemia ,. We have not performed the detection of class I grouped KIT mutation, which was reported to be coexpressed with AML1-ETO with poor prognosis . Long duration investigations were not possible due to budget constraints and the time needed to understand and generalize the findings.
| Conclusion|| |
There is a high frequency of AML1-ETO in the population studied. The prevalence of AML1-ETO in the Indian population is almost the same, as per the global report, but the remission rate is a bit lower, and the underlying causes have not been fully understood yet. One striking observation is the coprevalence of NPM1 in patients with AML1-ETO. The coprevalence of NPM1 mutation in AML1-ETO is higher, but no significant association is correlated. In several epithelial cancers, EGFR overexpression indicates poor prognosis, but, on the basis of the findings of this study, it is observed that the clinical course of AML1-ETO is unlikely to be influenced by EGFR expression. The overall median survival of AML1-ETO cases was more than 23 months in this study. White blood counts were more in AML1-ETO with NPM1 mutants compared with AML1-ETO with NPM1 wild types. Larger prospective studies may be carried out with longer follow-up for a clearer understanding and generalizing the above findings.
The authors are thankful to the Department of Biotechnology, Ministry of Science and Technology, Government of India, for their financial assistance for this project (BT/348/NE/TBP/2012).
Financial support and sponsorship
Department of Biotechnology, Ministry of Science and Technology, Government of India (BT/348/NE/TBP/2012).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]