Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis

Ryoichi Ono, Hideaki Nakajima, Katsutoshi Ozaki, Hidetoshi Kumagai, Toshiyuki Kawashima, Tomohiko Taki, Toshio Kitamura, Yasuhide Hayashi, Tetsuya Nosaka

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Abstract

The mechanisms by which mixed-lineage leukemia (MLL) fusion products resulting from in utero translocations in 11q23 contribute to leukemogenesis and infant acute leukemia remain elusive. It is still controversial whether the MLL fusion protein is sufficient to induce acute leukemia without additional genetic alterations, although carcinogenesis in general is known to result from more than 1 genetic disorder accumulating during a lifetime. Here we demonstrate that the fusion partner-mediated homooligomerization of MLL-SEPT6 is essential to immortalize hematopoietic progenitors in vitro. MLL-SEPT6 induced myeloproliferative disease with long latency in mice, but not acute leukemia, implying that secondary genotoxic events are required to develop leukemia. We developed in vitro and in vivo model systems of leukemogenesis by MLL fusion proteins, where activated FMS-like receptor tyrosine kinase 3 (FLT3) together with MLL-SEPT6 not only transformed hematopoietic progenitors in vitro but also induced acute biphenotypic or myeloid leukemia with short latency in vivo. In these systems, MLL-ENL, another type of the fusion product that seems to act as a monomer, also induced the transformation in vitro and leukemogenesis in vivo in concert with activated FLT3. These findings show direct evidence for a multistep leukemogenesis mediated by MLL fusion proteins and may be applicable to development of direct MLL fusion-targeted therapy.

Original languageEnglish (US)
Pages (from-to)919-929
Number of pages11
JournalJournal of Clinical Investigation
Volume115
Issue number4
DOIs
StatePublished - Apr 2005

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Myeloid-Lymphoid Leukemia Protein
Receptor Protein-Tyrosine Kinases
Dimerization
Leukemia
Inborn Genetic Diseases
Acute Myeloid Leukemia

ASJC Scopus subject areas

  • Medicine(all)

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Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. / Ono, Ryoichi; Nakajima, Hideaki; Ozaki, Katsutoshi; Kumagai, Hidetoshi; Kawashima, Toshiyuki; Taki, Tomohiko; Kitamura, Toshio; Hayashi, Yasuhide; Nosaka, Tetsuya.

In: Journal of Clinical Investigation, Vol. 115, No. 4, 04.2005, p. 919-929.

Research output: Contribution to journalArticle

Ono, R, Nakajima, H, Ozaki, K, Kumagai, H, Kawashima, T, Taki, T, Kitamura, T, Hayashi, Y & Nosaka, T 2005, 'Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis', Journal of Clinical Investigation, vol. 115, no. 4, pp. 919-929. https://doi.org/10.1172/JCI200522725
Ono, Ryoichi ; Nakajima, Hideaki ; Ozaki, Katsutoshi ; Kumagai, Hidetoshi ; Kawashima, Toshiyuki ; Taki, Tomohiko ; Kitamura, Toshio ; Hayashi, Yasuhide ; Nosaka, Tetsuya. / Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 4. pp. 919-929.
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