Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9

AUTOR(ES)

Ayton, Paul M.

FONTE

Cold Spring Harbor Laboratory Press

RESUMO

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.

Documentos Relacionados

• Hoxa9 and Meis1 Are Key Targets for MLL-ENL-Mediated Cellular Immortalization
• HOXA9 Forms Triple Complexes with PBX2 and MEIS1 in Myeloid Cells
• Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: Potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia
• Eukaryotic Translation Initiation Factor 4E Activity Is Modulated by HOXA9 at Multiple Levels
• Repression by HoxA7 is mediated by the homeodomain and the modulatory action of its N-terminal-arm residues.