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Fulltext Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia

Mat Yusoff Y, Ahid F, Abu Seman Z, Abdullah J, Kamaluddin NR, Esa E, et al.

Mol Cytogenet, 2021 Sep 24;14(1):45.
PMID: 34560908 DOI: 10.1186/s13039-021-00561-2

BACKGROUND: Relapsed acute myeloid leukemia (AML) is associated with the acquisition of additional somatic mutations which are thought to drive phenotypic adaptability, clonal selection and evolution of leukemic clones during treatment. We performed high throughput exome sequencing of matched presentation and relapsed samples from 6 cytogenetically normal AML (CN-AML) patients treated with standard remission induction chemotherapy in order to contribute with the investigation of the mutational landscape of CN-AML and clonal evolution during AML treatment.
RESULT: A total of 24 and 32 somatic variants were identified in presentation and relapse samples respectively with an average of 4.0 variants per patient at presentation and 5.3 variants per patient at relapse, with SNVs being more frequent than indels at both disease stages. All patients have somatic variants in at least one gene that is frequently mutated in AML at both disease presentation and relapse, with most of these variants are classic AML and recurrent hotspot mutations including NPM1 p.W288fs, FLT3-ITD, NRAS p.G12D and IDH2 p.R140Q. In addition, we found two distinct clonal evolution patterns of relapse: (1) a leukemic clone at disease presentation acquires additional mutations and evolves into the relapse clone after the chemotherapy; (2) a leukemic clone at disease presentation persists at relapse without the addition of novel somatic mutations.
CONCLUSIONS: The findings of this study suggest that the relapse-initiating clones may pre-exist prior to therapy, which harbor or acquire mutations that confer selective advantage during chemotherapy, resulting in clonal expansion and eventually leading to relapse.
Characterization of New Alpha Zero (α0) Thalassaemia Deletion (--GB) among Malays in Malaysian Population

Yasin NM, Abdul Hamid FS, Hassan S, Mat Yusoff Y, Mohd Sahid EN, Esa E

Diagnostics (Basel), 2023 Oct 23;13(20).
PMID: 37892108 DOI: 10.3390/diagnostics13203286

Malaysia is a multicultural and multiethnic country comprising numerous ethnic groups. From the total population of 32.7 million, Malays form the bulk of the Bumiputera in Malaysia comprise about 69.9%, followed by Chinese 22.8%, Indian 6.6%, and others 0.7%. The heterogeneous population and increasing numbers of non-citizens in this country affects the heterogeneity of genetic diseases, diversity, and heterogeneity of thalassaemia mutations. Alpha (α)-thalassaemia is an inherited haemoglobin disorder characterized by hypochromic microcytic anaemia caused by a quantitative reduction in the α-globin chain. A majority of the α-thalassaemia are caused by deletions in the α-globin gene cluster. Among Malays, the most common deletional alpha thalassaemia is -α3.7 deletion followed by --SEA deletion. We described the molecular characterization of a new --GB deletion in our population, involving both alpha genes in cis. Interestingly, we found that this mutation is unique among Malay ethnicities. It is important to diagnose this deletion because of the 25% risk of Hb Bart's with hydrops fetalis in the offspring when in combination with another α0- thalassaemia allele. MLPA is a suitable method to detect unknown and uncommon deletions and to characterize those cases which remain unresolved after a standard diagnostic approach.
Prevalence of BCR-ABL T315I Mutation in Malaysian Patients with Imatinib-Resistant Chronic Myeloid Leukemia

Mat Yusoff Y, Abu Seman Z, Othman N, Kamaluddin NR, Esa E, Zulkiply NA, et al.

Asian Pac J Cancer Prev, 2018 Dec 25;19(12):3317-3320.
PMID: 30583336

Objective: Chronic Myeloid Leukemia (CML) is caused by a reciprocal translocation between chromosomes 9
and 22, t(9;22) (q34;q11) which encodes for the BCR-ABL fusion protein. Discovery of Imatinib Mesylate (IM) as
first line therapy has brought tremendous improvement in the management of CML. However, emergence of point
mutations within the BCR-ABL gene particularly T315I mutation, affects a common BCR-ABL kinase contact residue
which impairs drug binding thus contribute to treatment resistance. This study aims to investigate the BCR-ABL T315I
mutation in Malaysian patients with CML. Methods: A total of 285 patients diagnosed with CML were included in this
study. Mutation detection was performed using qualitative real-time PCR (qPCR). Results: Fifteen out of 285 samples
(5.26%) were positive for T315I mutations after amplification with real-time PCR assay. From the total number of
positive samples, six patients were in accelerated phase (AP), four in chronic phase (CP) and five in blast crisis (BC).
Conclusion: Mutation testing is recommended for choosing various tyrosine kinase inhibitors (TKIs) to optimize
outcomes for both cases of treatment failure or suboptimal response to imatinib. Therefore, detection of T315I mutation
in CML patients are clinically useful in the selection of appropriate treatment strategies to prevent disease progression.
Fulltext Identification of FLT3 and NPM1 Mutations in Patients with Acute Myeloid Leukaemia

Mat Yusoff Y, Abu Seman Z, Othman N, Kamaluddin NR, Esa E, Zulkiply NA, et al.

Asian Pac J Cancer Prev, 2019 06 01;20(6):1749-1755.
PMID: 31244296 DOI: 10.31557/APJCP.2019.20.6.1749

Objective: The most frequent acquired molecular abnormalities and important prognostic indicators in patients
with Acute Myeloid Leukaemia (AML) are fms-like tyrosine kinase-3 gene (FLT3) and nucleophosmin-1 (NPM1)
mutations. Our study aims to develop a cost effective and comprehensive in-house conventional PCR method for
detection of FLT3-ITD, FLT3-D835 and NPM1 mutations and to evaluate the frequency of these mutations in patients
with cytogenetically normal (CN) AML in our population. Methods: A total of 199 samples from AML patients (95
women, 104 men) were included in the study. Mutation analyses were performed using polymerase chain reaction
(PCR) and gene sequencing. Result: Sixty-eight patients were positive for the mutations. FLT3-ITD mutations were
detected in 32 patients (16.1%), followed by FLT3-D835 in 5 (2.5%) and NPM1 in 54 (27.1%). Double mutations of
NPM1 and FLT3-ITD were detected in 23 cases (11.6%). Assays validation were performed using Sanger sequencing
and showed 100% concordance with in house method. Conclusion: The optimized in-house PCR assays for the
detection of FLT3-ITD, FLT3-D835 and NPM1 mutations in AML patients were robust, less labour intensive and cost
effective. These assays can be used as diagnostic tools for mutation detection in AML patients since identification of
these mutations are important for prognostication and optimization of patient care.
Whole-Exome Sequencing of ETV6/RUNX1 in Four Childhood Acute Lymphoblastic Leukaemia Cases

Zakaria Z, Othman N, Ismail A, Kamaluddin NR, Esa E, Abdul Rahman EJ, et al.

Asian Pac J Cancer Prev, 2017 04 01;18(4):1169-1175.
PMID: 28548470

Background: ETV6/RUNX1 gene fusion is the most frequently seen chromosomal abnormality in childhood acute
lymphobastic leukamia (ALL). However, additional genetic changes are known to be required for the development of
this type of leukaemia. Therefore, we here aimed to assess the somatic mutational profile of four ALL cases carrying the
ETV6/RUNX1 fusion gene using whole-exome sequencing. Methods: DNA was isolated from bone marrow samples
using a QIAmp DNA Blood Mini kit and subsequently sequenced using the Illumina MiSeq system. Results: We
identified 12,960 to17,601 mutations in each sample, with a total of 16,466 somatic mutations in total. Some 15,533
variants were single nucleotide polymorphisms (SNPs), 129 were substitutions, 415 were insertions and 389 were
deletions. When taking into account the coding region and protein impact, 1,875 variants were synonymous and 1,956
were non-synonymous SNPs. Among non-synonymous SNPs, 1,862 were missense, 13 nonsense, 35 frameshifts, 11
nonstop, 3 misstart, 15 splices disrupt and 17 in-frame indels. A total of 86 variants were located in leukaemia-related
genes of which 32 variants were located in the coding regions of GLI2, SP140, GATA2, SMAD5, KMT2C, CDH17,
CDX2, FLT3, PML and MOV10L1. Conclusions: Detection and identification of secondary genetic alterations are
important in identifying new therapeutic targets and developing rationally designed treatment regimens with less
toxicity in ALL patients.
Fulltext Molecular and hematological studies in a cohort of beta zero South East Asia deletion (β°-thal SEA) from Malaysian perspective

Yasin NM, Abdul Hamid FS, Hassan S, Sudin A, Yassim H, Mohd Sahid EN, et al.

Front Pediatr, 2022;10:974496.
PMID: 36533237 DOI: 10.3389/fped.2022.974496

ABSTRACT: We report the haematological parameters and molecular characterization of beta zero (β°) South East Asia (SEA) deletion in the HBB gene cluster with unusually high levels of Hb F compared to a classical heterozygous beta zero (β°)-thalassaemia.
METHODS: Retrospective study on 17 cases of (β°) South East Asia (SEA) deletion from 2016 to 2019 referred to Institute for Medical Research were conducted. The clinical information and haematological profiles were evaluated. The mutation was analyzed, and the results were compared with other β°-thalassaemia groups. For HBB gene genotyping, all the cases were subjected for multiplex gap-PCR, 5 cases were subjected for HBB gene sequencing for exclusion of compound heterozygous with other beta variants. Co-inheritance of α-thalassaemia were determined using multiplex gap-PCR and multiplex ARMS-PCR.
RESULTS: Seventeen cases were positive for β°-thal SEA deletion. Fifteen cases were heterozygous and two were compound heterozygous for β°-thal SEA deletion. The results were compared with 182 cases of various heterozygous β° deletions and mutations. The mean Hb for heterozygous β°-thal SEA deletion (13.44 ± 1.45 g/dl) was normal and significantly higher than heterozygous IVS 1-1 and Codon 41/42 (post hoc test, p
Construction of a microRNA-mRNA Regulatory Network in De Novo Cytogenetically Normal Acute Myeloid Leukemia Patients

Esa E, Hashim AK, Mohamed EHM, Zakaria Z, Abu Hassan AN, Mat Yusoff Y, et al.

Genet Test Mol Biomarkers, 2021 Mar;25(3):199-210.
PMID: 33734890 DOI: 10.1089/gtmb.2020.0182

Background: The association between dysregulated microRNAs (miRNAs) and acute myeloid leukemia (AML) is well known. However, our understanding of the regulatory role of miRNAs in the cytogenetically normal AML (CN-AML) subtype pathway is still poor. The current study integrated miRNA and mRNA profiles to explore novel miRNA-mRNA interactions that affect the regulatory patterns of de novo CN-AML. Methods: We utilized a multiplexed nanoString nCounter platform to profile both miRNAs and mRNAs using similar sets of patient samples (n = 24). Correlations were assessed, and an miRNA-mRNA network was constructed. The underlying biological functions of the mRNAs were predicted by gene enrichment. Finally, the interacting pairs were assessed using TargetScan and microT-CDS. We identified 637 significant negative correlations (false discovery rate <0.05). Results: Network analysis revealed a cluster of 12 miRNAs representing the majority of mRNA targets. Within the cluster, five miRNAs (miR-495-3p, miR-185-5p, let-7i-5p, miR-409-3p, and miR-127-3p) were posited to play a pivotal role in the regulation of CN-AML, as they are associated with the negative regulation of myeloid leukocyte differentiation, negative regulation of myeloid cell differentiation, and positive regulation of hematopoiesis. Conclusion: Three novel interactions in CN-AML were predicted as let-7i-5p:HOXA9, miR-495-3p:PIK3R1, and miR-495-3p:CDK6 may be responsible for regulating myeloid cell differentiation in CN-AML.