Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9.
Transcriptional deregulation through the production of dominant-acting chimeric transcription factors derived from chromosomal translocations is a common theme in the pathogenesis of acute leukemias; however, the essential target genes for acute leukemogenesis are unknown. We demonstrate here that primary myeloid progenitors immortalized by various MLL oncoproteins exhibit a characteristic Hoxa gene cluster expression profile, which reflects that preferentially expressed in the myeloid clonogenic progenitor fraction of normal bone marrow. Continued maintenance of this MLL-dependent Hoxa gene expression profile is associated with conditional MLL-associated myeloid immortalization. Moreover, Hoxa7 and Hoxa9 were specifically required for efficient in vitro myeloid immortalization by an MLL fusion protein but not other leukemogenic fusion proteins. Finally, in a bone marrow transduction/transplantation model, Hoxa9 is essential for MLL-dependent leukemogenesis in vivo, a primary requirement detected at the earliest stages of disease initiation. Thus, a genetic reliance on Hoxa7 and Hoxa9 in MLL-mediated transformation demonstrates a gain-of-function mechanism for MLL oncoproteins as upstream constitutive activators that promote myeloid transformation via a Hox-dependent mechanism.
Ayton
Paul M
PM
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Cleary
Michael L
ML
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D011519:Proto-Oncogenes; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C115962:HOXA7 protein, human; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase