DNMT3A co-mutation is required for FLT3-ITD as an adverse prognostic indicator in intermediate-risk cytogenetic group AML

References

• Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405.
   PubMed Web of Science ®Google Scholar
• Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–2221.
   PubMed Web of Science ®Google Scholar
• Reilly JT. FLT3 and its role in the pathogenesis of acute myeloid leukaemia. Leuk Lymphoma. 2003;44:1–7.
   PubMed Web of Science ®Google Scholar
• Panagiotis D, Kottaridis REG, Marion E, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research CouncilAML10 and 12 trials. Blood. 2001;98:1752–1759.
   PubMed Web of Science ®Google Scholar
• Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372–4380.
   PubMed Web of Science ®Google Scholar
• Kiyoi H, Towatari M, Yokota S, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12:1333–1337.
   PubMed Web of Science ®Google Scholar
• Garg M, Nagata Y, Kanojia D, et al. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood. 2015;126:2491–2501.
   PubMed Web of Science ®Google Scholar
• Wakita S, Yamaguchi H, Omori I, et al. Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia. 2013;27:1044–1052.
   PubMed Web of Science ®Google Scholar
• Blau O, Berenstein R, Sindram A, et al. Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia. Leuk Lymphoma. 2013;54:145–152.
   PubMed Web of Science ®Google Scholar
• Yan XJ, Xu J, Gu ZH, et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011;43:309–315.
   PubMed Web of Science ®Google Scholar
• Renneville A, Boissel N, Nibourel O, et al. Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia. 2012;26:1247–1254.
   PubMed Web of Science ®Google Scholar
• Yang L, Rau R, Goodell MA. DNMT3A in haematological malignancies. Nat Rev Cancer. 2015;15:152–165.
   PubMed Web of Science ®Google Scholar
• Shlush LI, Zandi S, Mitchell A, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506:328–333.
   PubMed Web of Science ®Google Scholar
• Yang L, Liu Y, Zhu L, et al. DNMT3A R882 mutation is associated with elevated expression of MAFB and M4/M5 immunophenotype of acute myeloid leukemia blasts. Leuk Lymphoma. 2015;56:2914–2922.
   PubMed Web of Science ®Google Scholar
• Reinig Y EF, Traer E, Arora R, et al. Targeted next-generation sequencing in myelodysplastic syndrome and chronic myelomonocytic leukemia aids diagnosis in challenging cases and identifies frequent spliceosome mutations in transformed acute myeloid leukemia. Am J Clin Pathol. 2016;145:497–506.
   PubMed Web of Science ®Google Scholar
• Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127:29–41.
   PubMed Web of Science ®Google Scholar
• Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–447.
   PubMed Web of Science ®Google Scholar
• Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124:3441–3449.
   PubMed Web of Science ®Google Scholar
• Gale RE, Lamb K, Allen C, et al. Simpson’s paradox and the impact of different DNMT3A mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol. 2015;33:2072–2083.
   PubMed Web of Science ®Google Scholar
• Gaidzik VI, Schlenk RF, Paschka P, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood. 2013;121:4769–4777.
   PubMed Web of Science ®Google Scholar
• Bhatnagar B, Eisfeld AK, Nicolet D, et al. Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia. Br J Haematol. 2016;175:226–236.
   PubMed Web of Science ®Google Scholar
• Klco JM, Miller CA, Griffith M, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA. 2015;314:811–822.
   PubMed Web of Science ®Google Scholar
• Hirsch P, Tang R, Abermil N, et al. Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia. Haematologica. 2017;102:1227–1237.
   PubMed Web of Science ®Google Scholar
• Rönnerblad M, Andersson R, Olofsson T, et al. Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation. Blood. 2014;123:e79–e89.
   PubMed Web of Science ®Google Scholar
• Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2012;44:23–31.
   Web of Science ®Google Scholar
• Jost E, Lin Q, Weidner CI, et al. Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia. Leukemia. 2014;28:1227–1234.
   PubMed Web of Science ®Google Scholar
• Meyer SE, Qin T, Muench DE, et al. DNMT3A haploinsufficiency transforms FLT3ITD myeloproliferative disease into a rapid, spontaneous, and fully penetrant acute myeloid leukemia. Cancer Discov. 2016;6:501–515.
   PubMed Web of Science ®Google Scholar
• Poitras JL, Heiser D, Li L, et al. Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model. Oncotarget. 2016;7:69124–69135.
   PubMed Web of Science ®Google Scholar
• Rodriguez B, Luo M, Jeong M, et al. Dnmt3a-deletion accelerates FLT3-ITD malignancies in mice by hypomethylation of enhancer sites and activating stem cell programs: implications for therapy. Blood. 2013;122:595–595.
   Web of Science ®Google Scholar
• Wu H, Wang A, Qi Z, et al. Discovery of a highly potent FLT3 kinase inhibitor for FLT3-ITD-positive AML. Leukemia. 2016;30:2112–2116.
   PubMed Web of Science ®Google Scholar
• Chang E, Ganguly S, Rajkhowa T, et al. The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells. Leukemia. 2016;30:1025–1032.
   PubMed Web of Science ®Google Scholar
• Huang A, Ju HQ, Liu K, et al. Metabolic alterations and drug sensitivity of tyrosine kinase inhibitor resistant leukemia cells with a FLT3/ITD mutation. Cancer Lett. 2016;377:149–157.
   PubMed Web of Science ®Google Scholar