Publications by authors named "Chetsada Boonthimat"

4 Publications

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Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients.

J Hematol Oncol 2012 Mar 7;5. Epub 2012 Mar 7.

Department of Medicine, Mahidol University, Bangkok, Thailand.

Background: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to α-ketoglutarate. Acquired somatic mutations of IDH1 and IDH2 have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases.

Methods: Two-hundred and thirty newly diagnosed AML patients were analyzed for the presence of IDH1 and IDH2 heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the IDH mutational status. Coexisting mutations such as FLT3, PML-RARA, RAS, AML1, and NPM1 mutations were additionally explored.

Results: The prevalence of IDH1 and IDH2 mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among IDH1-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in IDH2-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual IDH1 and IDH2 mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had IDH mutations. Half of the IDH-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, IDH1- and IDH2-mutated cases predominantly had NPM1 mutations (60-74%) as compared to the wild type (P < 0.001). Very few IDH-mutated cases had FLT3 and/or RAS abnormalities and none of them had AML1 mutations. Older age and higher median platelet counts were significantly associated with IDH2 mutations although the clinical impact of either IDH1 or IDH2 mutations on patients' overall survival could not be observed.

Conclusion: Overall, 19% of newly diagnosed AML patients had alterations of IDH genes. No patients concurrently carried both IDH1 and IDH2 mutations suggesting that these mutations were mutually exclusive. NPM1 mutation appears as a major coexisting genetic mutation in IDH-mutated patients. Our present data failed to support the prognostic relevance of IDH mutations although alterations of these metabolic genes potentially have an important role in leukemia development.
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http://dx.doi.org/10.1186/1756-8722-5-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320529PMC
March 2012

Unique CRF01_AE Gag CTL epitopes associated with lower HIV-viral load and delayed disease progression in a cohort of HIV-infected Thais.

PLoS One 2011 3;6(8):e22680. Epub 2011 Aug 3.

Department of Clinical Medicine, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan.

Cytotoxic T Lymphocytes (CTLs) play a central role in controlling HIV-replication. Although numerous CTL epitopes have been described, most are in subtype B or C infection. Little is known about CTL responses in CRF01_AE infection. Gag CTL responses were investigated in a cohort of 137 treatment-naïve HIV-1 infected Thai patients with high CD4+ T cell counts, using gIFN Enzyme-Linked Immunospot (ELISpot) assays with 15-mer overlapping peptides (OLPs) derived from locally dominant CRF01_AE Gag sequences. 44 OLPs were recognized in 112 (81.8%) individuals. Both the breadth and magnitude of the CTL response, particularly against the p24 region, positively correlated with CD4+ T cell count and inversely correlated with HIV viral load. The breadth of OLP response was also associated with slower progression to antiretroviral therapy initiation. Statistical analysis and single peptide ELISpot assay identified at least 17 significant associations between reactive OLP and HLA in 12 OLP regions; 6 OLP-HLA associations (35.3%) were not compatible with previously reported CTL epitopes, suggesting that these contained new CTL Gag epitopes. A substantial proportion of CTL epitopes in CRF01_AE infection differ from subtype B or C. However, the pattern of protective CTL responses is similar; Gag CTL responses, particularly against p24, control viral replication and slow clinical progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149616PMC
December 2011

WT1 mutations and polymorphisms in Southeast Asian acute myeloid leukemia.

Exp Mol Pathol 2011 Dec 23;91(3):682-6. Epub 2011 Jul 23.

Cancer Molecular Diagnostics Unit, Chulabhorn Hospital, Bangkok, Thailand.

Genomic alterations of the Wilms' Tumor 1 (WT1) gene have been reported to occur in patients with acute myeloid leukemia (AML). No data presently exists regarding the frequency of WT1 mutations in the Southeast Asian AML population. This study focused on WT1 exons 7-10 mutations and their correlation with other molecular markers and patients' characteristics. The zinc finger domain of WT1 gene covering exons 7-10 was directly sequenced. Six types of mutations were identified among 49 cases (12.24%); 4 localized on exon 7 and 2 on exon 9. Two novel mutations were identified including the insertion within codon 313 and codon 314. Patients harboring WT1 mutations seemed to have a younger age (29.5 vs 45.4 years), a higher white blood cell count (120.3 vs 19.8×10(9)/L), and a lower platelet count (54.2 vs 104.3×10(9)/L) as compared to those without the mutations although statistical differences could not be demonstrated. All exon 7 mutations were frameshift mutations and had NRAS mutation while exon 9 mutations were base substitutions and had FLT3-ITD mutation. Interestingly, the major allele for rs16754 single nucleotide polymorphism was G (25-homozygous and 6-heterozygous) which was in contrast to A in the Western reports. The frequency of WT1 mutation in the Southeast Asian AML was thus comparable to the figures reported from the West although the designated major allele for rs16754 polymorphism was different.
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http://dx.doi.org/10.1016/j.yexmp.2011.06.009DOI Listing
December 2011

Nucleophosmin mutation in Southeast Asian acute myeloid leukemia: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations.

Haematologica 2008 Oct 18;93(10):1565-9. Epub 2008 Jul 18.

Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

NPM1 mutations were investigated in 400 Southeast Asian leukemia patients and were detectable in 105 cases (26.25%) of acute myeloid leukemia but in no cases of acute lymphoid leukemia or chronic myeloid leukemia. Eight novel and 5 known mutations were identified. All predicted novel proteins shared the last five amino acids VSLRK with the similar gain of nuclear exporting signal motif as known variants. Older age, high white blood cell and platelet counts, normal cytogenetics, and CD34-negativity were associated with NPM1 mutation. FLT3 mutation was more frequent in mutant NPM1 than wild-type cases (56.8% vs. 25.6%) whereas RAS and AML1 mutations were rarely found. Overall survival analysis based on the NPM1/FLT3 mutational status revealed a better outcome for the NPM1-positive/FLT3-negative subgroup. We conclude that: i) NPM1 mutation represents a common genetic hallmark in Southeast Asian acute myeloid leukemia with a normal karyotype; ii) NPM1 mutants coexisted mainly with FLT3 mutants, but not RAS or AML1; iii) FLT3 mutation had a negative prognostic impact on patients with mutant NPM1.
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http://dx.doi.org/10.3324/haematol.12937DOI Listing
October 2008