TY - JOUR
T1 - Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation
AU - Ono, R.
AU - Kumagai, H.
AU - Nakajima, H.
AU - Hishiya, A.
AU - Taki, T.
AU - Horikawa, K.
AU - Takatsu, K.
AU - Satoh, T.
AU - Hayashi, Y.
AU - Kitamura, T.
AU - Nosaka, T.
N1 - Funding Information:
We thank Dr Guy Sauvageau (Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, Canada) for the plasmid harboring a fragment of Hoxa9, and Dr Yusuke Satoh (Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan) for technical advice. We are also grateful to R&D Systems for providing cytokines, and Brian Quinn for language assistance. This work was supported in part by Chugai Pharmaceutical Company Ltd, Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan, the Novartis Foundation (Japan) for the Promotion of Science and the Japan Leukaemia Research Fund.
PY - 2009/12
Y1 - 2009/12
N2 - 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.
AB - 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.
KW - MAP kinase
KW - MLL
KW - Ras
KW - leukemogenesis
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U2 - 10.1038/leu.2009.177
DO - 10.1038/leu.2009.177
M3 - Article
C2 - 19710696
AN - SCOPUS:74049101141
SN - 0887-6924
VL - 23
SP - 2197
EP - 2209
JO - Leukemia
JF - Leukemia
IS - 12
ER -