Garg, Manoj ORCID: 0000-0002-3492-2957, Nagata, Yasunobu, Kanojia, Deepika, Mayakonda, Anand ORCID: 0000-0003-1162-687X, Yoshida, Kenichi ORCID: 0000-0003-4612-2778, Keloth, Sreya Haridas, Zang, Zhi Jiang, Okuno, Yusuke ORCID: 0000-0003-3139-9272, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Miyano, Satoru ORCID: 0000-0002-1753-6616, Ding, Ling-Wen ORCID: 0000-0003-0022-1551, Alpermann, Tamara, Sun, Qiao-Yang ORCID: 0000-0002-9855-5586, Lin, De-Chen, Chien, Wenwen, Madan, Vikas, Liu, Li-Zhen, Tan, Kar-Tong, Sampath, Abhishek, Venkatesan, Subhashree, Inokuchi, Koiti, Wakita, Satoshi, Yamaguchi, Hiroki, Chng, Wee Joo, Kham, Shirley-Kow Yin, Yeoh, Allen Eng-Juh, Sanada, Masashi, Schiller, Joanna, Kreuzer, Karl-Anton, Kornblau, Steven M., Kantarjian, Hagop M., Haferlach, Torsten, Lill, Michael, Kuo, Ming-Chung, Shih, Lee-Yung, Blau, Igor-Wolfgang, Blau, Olga ORCID: 0000-0002-4304-5079, Yang, Henry, Ogawa, Seishi and Koeffler, H. Phillip (2015). Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood, 126 (22). S. 2491 - 2502. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

Full text not available from this repository.

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Garg, ManojUNSPECIFIEDorcid.org/0000-0002-3492-2957UNSPECIFIED
Nagata, YasunobuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kanojia, DeepikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayakonda, AnandUNSPECIFIEDorcid.org/0000-0003-1162-687XUNSPECIFIED
Yoshida, KenichiUNSPECIFIEDorcid.org/0000-0003-4612-2778UNSPECIFIED
Keloth, Sreya HaridasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zang, Zhi JiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okuno, YusukeUNSPECIFIEDorcid.org/0000-0003-3139-9272UNSPECIFIED
Shiraishi, YuichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chiba, KenichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tanaka, HirokoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miyano, SatoruUNSPECIFIEDorcid.org/0000-0002-1753-6616UNSPECIFIED
Ding, Ling-WenUNSPECIFIEDorcid.org/0000-0003-0022-1551UNSPECIFIED
Alpermann, TamaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sun, Qiao-YangUNSPECIFIEDorcid.org/0000-0002-9855-5586UNSPECIFIED
Lin, De-ChenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chien, WenwenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madan, VikasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, Li-ZhenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Kar-TongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sampath, AbhishekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venkatesan, SubhashreeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Inokuchi, KoitiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wakita, SatoshiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yamaguchi, HirokiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chng, Wee JooUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kham, Shirley-Kow YinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yeoh, Allen Eng-JuhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanada, MasashiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schiller, JoannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuzer, Karl-AntonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornblau, Steven M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kantarjian, Hagop M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haferlach, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lill, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuo, Ming-ChungUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shih, Lee-YungUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blau, Igor-WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blau, OlgaUNSPECIFIEDorcid.org/0000-0002-4304-5079UNSPECIFIED
Yang, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ogawa, SeishiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeffler, H. PhillipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-386724
DOI: 10.1182/blood-2015-05-646240
Journal or Publication Title: Blood
Volume: 126
Number: 22
Page Range: S. 2491 - 2502
Date: 2015
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INTERNAL TANDEM DUPLICATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; SQUAMOUS-CELL CARCINOMA; CLONAL EVOLUTION; DNMT3A MUTATIONS; NORMAL HEMATOPOIESIS; RECURRENT MUTATIONS; CANCER GENOMES; ADULT PATIENTS; LUNG-CANCERMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/38672

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item