Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

R. Ono, H. Kumagai, H. Nakajima, A. Hishiya, T. Taki, K. Horikawa, K. Takatsu, T. Satoh, Y. Hayashi, T. Kitamura, T. Nosaka

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia.

Original languageEnglish
Pages (from-to)2197-2209
Number of pages13
JournalLeukemia
Volume23
Issue number12
DOIs
Publication statusPublished - 2009 Dec

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Myeloid-Lymphoid Leukemia Protein
Leukemia
Receptor Protein-Tyrosine Kinases
Oncogene Fusion
STAT5 Transcription Factor
Mutation

Keywords

  • leukemogenesis
  • MAP kinase
  • MLL
  • Ras

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Medicine(all)

Cite this

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation. / Ono, R.; Kumagai, H.; Nakajima, H.; Hishiya, A.; Taki, T.; Horikawa, K.; Takatsu, K.; Satoh, T.; Hayashi, Y.; Kitamura, T.; Nosaka, T.

In: Leukemia, Vol. 23, No. 12, 12.2009, p. 2197-2209.

Research output: Contribution to journalArticle

Ono, R, Kumagai, H, Nakajima, H, Hishiya, A, Taki, T, Horikawa, K, Takatsu, K, Satoh, T, Hayashi, Y, Kitamura, T & Nosaka, T 2009, 'Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation', Leukemia, vol. 23, no. 12, pp. 2197-2209. https://doi.org/10.1038/leu.2009.177
Ono, R. ; Kumagai, H. ; Nakajima, H. ; Hishiya, A. ; Taki, T. ; Horikawa, K. ; Takatsu, K. ; Satoh, T. ; Hayashi, Y. ; Kitamura, T. ; Nosaka, T. / Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation. In: Leukemia. 2009 ; Vol. 23, No. 12. pp. 2197-2209.
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