Wainscoat, J.S. (James S.)

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20122

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    Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics
    (2012) Kondo, T. (Toshinori); McDonald, E.J. (Emma Jane); Perez, C. (Cristina); Fernandez-Mercado, M. (Marta); Wainscoat, J.S. (James S.); Pellagatti, A. (Andrea); Davies, C. (Carwyn); Boultwood, J. (Jacqueline); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Yip, B.H. (Bon Ham); Odero, M.D. (Maria Dolores); Aguirre-Ena, X. (Xabier); Killick, S. (Sally)
    Abstract Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML
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    TET2 mutations are associated with specific 5-methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia
    (Public Library of Science, 2012) Perez, C. (Cristina); Cigudosa, J.C. (Juan Cruz); Fernandez-Mercado, M. (Marta); Wainscoat, J.S. (James S.); Alvarez, S. (Sara); Martinez-Calle, N. (Nicolas); Garate, L. (Leire); Rifon, J. J. (Jose J.); Delabesse, E. (Eric); Boultwood, J. (Jacqueline); Cross, N.C.P. (Nicholas C.P.); Varea, S. (Sara); Prosper-Cardoso, F. (Felipe); Segura, V. (Víctor); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)
    Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has been recently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.