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Profiling of Somatic Mutations of Acute Myeloid Leukemia, FLT3-ITD Subgroup at Diagnosis and Relapse. (Blood, Oct 2015)

Garg M1, Nagata Y2, Kanojia D3, M T A3, Yoshida K2, Keloth SH3, Jiang ZZ3, Okuno Y4, Shiraishi Y5, Chiba K5, Tanaka H6, Miyano S6, Ding LW3, Alpermann T7, Sun QY3, Lin DC3, Chien W3, Madan V3, Liu LZ3, Tan KT3, Sampath A3, Venkatesan S3, Inokuchi K8, Wakita S8, Yamaguchi H8, Chng WJ3, Kham SY9, Yeoh AE9, Sanada M10, Schiller J11, Kreuzer KA11, Kornblau SM12, Kantarjian HM13, Haferlach T7, Lill M14, Kuo MC15, Shih LY15, Blau IW16, Blau O16, Yang H3, Ogawa S2, Koeffler HP14.

1 Cancer Science Institute of Singapore, National University of Singapore, Singapore
2 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
3 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore;
4 Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan;
5 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
6 Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
7 MLL Munich Leukemia Laboratory, MLL Munich Leukemia Laboratory, Munich, Germany;
8 Department of Hematology, Nippon Medical School, Tokyo, Japan;
9 Department of Paediatrics, National University Health System, Singapore, Singapore;
10 Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan;
11 Department I of Internal Medicine, University at Cologne, Cologne, Germany;
12 Department of Leukemia – Unit 428, M.D. Anderson Cancer Center, Houston, TX, United States;
13 Section of Molecular Hematology & Therapy, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States;
14 Cedars-Senai Medical Center, Division of Hematology/Oncology, University of California Los Angeles, School of Medicine, Los Angeles, CA, United States;
15 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan;
16 Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Berlin, Germany.

Abstract:
Acute myeloid leukemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify mutational spectrum associated with relapse, whole exome sequencing was performed on 13 matched diagnosis, relapse and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared to solid tumors. Recurrent mutations occur in genes related to DNA-methylation, chromatin, histone-methylation, myeloid transcription factors, signaling, adhesion, cohesin-complex and spliceosome-complex. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biologic relationship. In addition, we identify mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in nine genes are observed in the relapse specific phase. DNMT3A mutations are the most stable mutations and this DNMT3A transformed clone can be present even in morphological complete remissions. Of note, all matched trios AML samples share at least one genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse either: (a) the founder clone recurs or (b) a subclone of the founder clone escapes from the induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations display increase in transversions. Functional assays demonstrate both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.