Discovery and validation of expression data for the Genomics of Acute Myeloid Leukemia Program at Washington University

Activating mutations in tyrosine kinase (TK) genes (e.g. FLT3 and KIT) are found in more than 30% of patients with de novo acute myeloid leukemia (AML); many groups have speculated that mutations in other TK genes may be present in the remaining 70%. We performed high-throughput re-sequencing of the kinase domains of 26 TK genes (11 receptor TK and 15 cytoplasmic TK) that are expressed in most AML patients, using genomic DNA from the bone marrow (tumor) and matched skin biopsy samples (germline) from 94 patients with de novo AML; sequence variants were validated in an additional 94 AML tumor samples (14.3 million base pairs of sequence were obtained and analyzed). We identified known somatic mutations in FLT3, KIT, and JAK2 TK genes at the expected frequencies, and found four novel somatic mutations, JAK1V623A, JAK1T478S, DDR1A803V and NTRK1S677N, once each in four respective patients out of 188 tested. We also identified novel germline sequence changes encoding amino acid substitutions (i.e. non-synonymous changes) in 14 TK genes, including TYK2, which had the largest number of non-synonymous sequence variants (11 total detected). Additional studies will be required to define the roles that these somatic and germline TK gene variants play in AML pathogenesis.

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Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont DH, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ