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

Manoj Garg, Yasunobu Nagata, Deepika Kanojia, Anand Mayakonda, Kenichi Yoshida, Sreya Haridas Keloth, Zhi Jiang Zang, Yusuke Okuno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Ling Wen Ding, Tamara Alpermann, Qiao Yang Sun, De Chen Lin, Wenwen Chien, Vikas Madan, Li Zhen Liu, Kar Tong TanAbhishek Sampath, Subhashree Venkatesan, Koiti Inokuchi, Satoshi Wakita, Hiroki Yamaguchi, Wee Joo Chng, Shirley Kow Yin Kham, Allen Eng Juh Yeoh, Masashi Sanada, Joanna Schiller, Karl Anton Kreuzer, Steven M. Kornblau, Hagop M. Kantarjian, Torsten Haferlach, Michael Lill, Ming Chung Kuo, Lee Yung Shih, Igor Wolfgang Blau, Olga Blau, Henry Yang, Seishi Ogawa, H. Phillip Koeffler

Research output: Contribution to journalArticlepeer-review

170 Scopus citations


Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologicmalignancy with a grave prognosis. To identify the mutational spectrumassociated with relapse, whole-exomesequencing was performed on 13matched 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, histonemethylation, 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 identifiedmutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutationsare themost stablemutations,and thisDNMT3A-transformed clonecan be present eveninmorphologic 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.

Original languageEnglish
Pages (from-to)2491-2501
Number of pages11
Issue number22
StatePublished - 26 Nov 2015
Externally publishedYes


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