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

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 homo-oligomerization 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.
Authors	Ryoichi Ono, Hideaki Nakajima, Katsutoshi Ozaki, Hidetoshi Kumagai, Toshiyuki Kawashima, Tomohiko Taki, Toshio Kitamura, Yasuhide Hayashi, Tetsuya Nosaka
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 4 Pg. 919-29 (Apr 2005) ISSN: 0021-9738 [Print] United States
PMID	15761502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cytoskeletal Proteins DNA-Binding Proteins KMT2A protein, human Oncogene Proteins, Fusion Proto-Oncogene Proteins Recombinant Fusion Proteins Transcription Factors Myeloid-Lymphoid Leukemia Protein Histone-Lysine N-Methyltransferase Kmt2a protein, mouse FLT3 protein, human Flt3 protein, mouse Receptor Protein-Tyrosine Kinases fms-Like Tyrosine Kinase 3 GTP-Binding Proteins SEPTIN6 protein, human Septins
Topics	Animals Cell Transformation, Neoplastic Cell Transplantation Cells, Cultured Cytoskeletal Proteins DNA Damage DNA-Binding Proteins (chemistry, genetics, metabolism) Dimerization Enzyme Activation GTP-Binding Proteins (chemistry, genetics, metabolism) Hematopoietic Stem Cells (cytology, metabolism) Histone-Lysine N-Methyltransferase Humans Infant Leukemia, Myeloid, Acute (metabolism) Liver (pathology, physiology) Mice Mice, Inbred C57BL Myeloid-Lymphoid Leukemia Protein Oncogene Proteins, Fusion (chemistry, genetics, metabolism) Protein Structure, Tertiary Proto-Oncogene Proteins (metabolism) Proto-Oncogenes (genetics) Receptor Protein-Tyrosine Kinases (metabolism) Recombinant Fusion Proteins (chemistry, genetics, metabolism) Septins Spleen (pathology, physiology) Transcription Factors (chemistry, genetics, metabolism) fms-Like Tyrosine Kinase 3

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