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Blood. 2015 Nov 26;126(22):2491-501. doi: 10.1182/blood-2015-05-646240. Epub 2015 Oct 5.

Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse.

Author information

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

Abstract

Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the 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. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that 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.

© 2015 by The American Society of Hematology.

PMID:
26438511
[PubMed - indexed for MEDLINE]
PMCID:
PMC4661172
[Available on 2016-11-26]
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