Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis.
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.
Ono
Ryoichi
R
Division of Hematopoietic Factors, The Institute of Medical Science, Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nakajima
Hideaki
H
Ozaki
Katsutoshi
K
Kumagai
Hidetoshi
H
Kawashima
Toshiyuki
T
Taki
Tomohiko
T
Kitamura
Toshio
T
Hayashi
Yasuhide
Y
Nosaka
Tetsuya
T
D000818:Animals; D002471:Cell Transformation, Neoplastic; D017690:Cell Transplantation; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008099:Liver / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011519:Proto-Oncogenes / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058112:Septins; D013154:Spleen / Q000473:pathology / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D019204:GTP-Binding Proteins; C436485:SEPTIN6 protein, human; D058112:Septins