MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice.
A specific association with mixed lineage leukemias suggests that MLL oncoproteins may selectively target early multipotent hematopoietic progenitors or stem cells. We demonstrate here that a representative MLL fusion protein, MLL-GAS7, impairs the differentiation and enhances the in vitro growth of murine hematopoietic cells with multipotent features. The multilineage differentiation potential of these cells was suggested by their immuno-phenotypes and transcriptional programs and confirmed by their ability to induce three pathologically distinct leukemias in mice, including an acute biphenotypic leukemia (ABL) that recapitulates the distinctive hallmark features of many MLL-associated leukemias in humans. This experimental modeling of ABL in mice highlights its origin from multipotential progenitors that arrest at a bipotential stage specifically targeted or induced by MLL oncogenes.
So
Chi Wai
CW
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Karsunky
Holger
H
Passegué
Emmanuelle
E
Cozzio
Antonio
A
Weissman
Irving L
IL
Cleary
Michael L
ML
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D015153:Blotting, Western; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D016130:Immunophenotyping; D007938:Leukemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D015514:Oncogene Proteins, Fusion / Q000494:pharmacology*; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors
D000954:Antigens, Surface; D016207:Cytokines; D004268:DNA-Binding Proteins; C114909:GAS7 protein, human; C485435:Gas7 protein, mouse; C497422:KMT2A protein, human; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse