Mat Yunus, Noraini
(2015)
FLT3, NPM1, DNMT3a and NRAS genes mutation in acute myeloid leukaemia in HUSM.
Masters thesis, Universiti Sains Malaysia.
Abstract
Acute myeloid leukaemia (AML) is a rare but the most common occurrence among
hematologic malignancy and associated with the greatest mortality in adults. FMS-like
tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and nucleophosmin 1 (NPM1)
mutations are the most common genes mutation found in adult AML and have been
associated with poor and good prognosis, respectively. Published data on the prevalence
of FLT3-ITD and NPM1 mutations of AML adult patients in Malaysia are not available
online. Thus, this study was conducted to determine the frequency of FLT3-ITD and
NPM1 mutation as well as FLT3-TKD, DNMT3a, and NRAS, the types of mutations,
two-years overall survival/median survival time of FLT3-ITD+/FLT3-ITD- and
NPM1+/NPM1- group, and the related clinical data for mutant FLT3-ITD and NPM1
within the adult Malaysian AML patients. In this study, the genomics DNA from 54
newly diagnosed adult AML patients were retrieved from Hospital Universiti Sains
Malaysia, Kelantan. Polymerase chain reaction followed by conformation sensitive gel
electrophoresis (PCR-CSGE) technique was used to detect gene mutations in AML. The
frequency of FLT3-ITD and NPM1 mutations were found to be 11% and 13%,
respectively which were less compared to published data. With respect to sequence
analysis, all of the mutant FLT3-ITD and NPM1 resulted in variety of amino acid
sequences in every case. Based on the analysis, two types of mutation have been
identified in FLT3 exon 14; ITD (six cases) and non-ITD (a single nucleotide deletion)
(one case). Both kind of mutations would disturb the juxtamembrane domain function in
FLT3 receptor, thus activate the continuous growth signal. Interestingly, a different
finding was found in NPM1 mutation. Although the mutation was identified in the
coding region of C-terminal domain, the mutation does not disturb the NPM nucleolar
localization signal (NoLs) motif. FLT3-ITD mutation was associated with a significantly
higher blast percentage (p-value = 0.008) and white blood cell count (p-value = 0.023)
than the FLT3 wild type. On the other hand, NPM1 mutation were found not to associate
with blast percentage and white blood cell count but occurred significantly higher in
female patients (p-value = 0.038). Mutation was not detected in FLT3-TKD, NRAS, and
DNMT3a genes. Two years overall survival (OS) analysis indicated no significant
difference in both group, FLT3-ITD+/FLT3-ITD- (p-value = 0.660) and NPM1+/NPM1-
(p-value = 0.714). Although the OS in FLT3-ITD+/FLT3-ITD- group showed not
significantly difference, the median OS of AML patients with the FLT3-ITD was shorter
than those with the wild type (9 versus 52 weeks, respectively). FLT3-ITD and NPM1
mutations were more prevalent in adult Malaysian AML patients compared to the other
genes; FLT3-TKD, DNMT3a, and NRAS.
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