Molecular pathogenesis of disease progression in MLL-rearranged AML

Shinichi Kotani, Akinori Yoda, Ayana Kon, Keisuke Kataoka, Yotaro Ochi, Yusuke Shiozawa, Cassandra Hirsch, June Takeda, Hiroo Ueno, Tetsuichi Yoshizato, Kenichi Yoshida, Masahiro M. Nakagawa, Yasuhito Nannya, Nobuyuki Kakiuchi, Takuji Yamauchi, Kosuke Aoki, Yuichi Shiraishi, Satoru Miyano, Takahiro Maeda, Jaroslaw P. MaciejewskiAkifumi Takaori-Kondo, Seishi Ogawa, Hideki Makishima

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3 Citations (Scopus)

Abstract

Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.

Original languageEnglish
Pages (from-to)612-624
Number of pages13
JournalLeukemia
Volume33
Issue number3
DOIs
Publication statusPublished - Mar 1 2019

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All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Kotani, S., Yoda, A., Kon, A., Kataoka, K., Ochi, Y., Shiozawa, Y., ... Makishima, H. (2019). Molecular pathogenesis of disease progression in MLL-rearranged AML. Leukemia, 33(3), 612-624. https://doi.org/10.1038/s41375-018-0253-3