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Ordering of Mutations in Acute Myeloid Leukemia with Partial Tandem Duplication of MLL (MLL-PTD). (Leukemia, Jul 2016)

Sun QY1, Ding LW1, Tan KT1, Chien W1, Mayakonda A1, Lin DC1,2, Loh XY1, Xiao JF1, Meggendorfer M3, Alpermann T3, Garg M1, Lim SL1, Madan V1, Hattori N1, Nagata Y4, Miyano S5,6, Yeoh AE1, Hou HA7, Jiang YY1, Takao S1, Liu LZ1, Tan SZ1, Lill M2, Hayashi M8, Kinoshita A8, Kantarjian HM9, Kornblau SM9, Ogawa S4, Haferlach T3, Yang H1, Koeffler HP1,2

1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
3MLL Munich Leukemia Laboratory, Munich, Germany.
4Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
6Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
7Division of Hematology, National Taiwan University Hospital, National Taiwan University, Taiwan.
8Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
9Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, USA.

Abstract:

Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutationsand to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTDpatients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferativemutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.

PMID: 27389053