Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ-TIF2 fusion.
Int J Hematol, 2014/1;99(1):21-31.
Shima H[1], Yamagata K, Aikawa Y, Shino M, Koseki H, Shimada H, Kitabayashi I
Affiliations
PMID: 24258712DOI: 10.1007/s12185-013-1466-x
Impact factor: 2.319
Abstract
Chromosomal translocations that involve the monocytic leukemia zinc finger (MOZ) gene are typically associated with human acute myeloid leukemia (AML) and often predict a poor prognosis. Overexpression of HOXA9, HOXA10, and MEIS1 was observed in AML patients with MOZ fusions. To assess the functional role of HOX upregulation in leukemogenesis by MOZ-TIF2, we focused on bromodomain-PHD finger protein 1 (BRPF1), a component of the MOZ complex that carries out histone acetylation for generating and maintaining proper epigenetic programs in hematopoietic cells. Immunoprecipitation analysis showed that MOZ-TIF2 forms a stable complex with BRPF1, and chromatin immunoprecipitation analysis showed that MOZ-TIF2 and BRPF1 interact with HOX genes in MOZ-TIF2-induced AML cells. Depletion of BRPF1 decreased the MOZ localization on HOX genes, resulting in loss of transformation ability induced by MOZ-TIF2. Furthermore, mutant MOZ-TIF2 engineered to lack histone acetyltransferase activity was incapable of deregulating HOX genes as well as initiating leukemia. These data indicate that MOZ-TIF2/BRPF1 complex upregulates HOX genes mediated by MOZ-dependent histone acetylation, leading to the development of leukemia. We suggest that activation of BRPF1/HOX pathway through MOZ HAT activity is critical for MOZ-TIF2 to induce AML.
MeSH terms
Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Cell Line, Tumor; Cell Transformation, Neoplastic; DNA-Binding Proteins; Disease Models, Animal; Gene Expression; Gene Knockdown Techniques; Histone Acetyltransferases; Homeobox A10 Proteins; Homeodomain Proteins; Humans; Leukemia; Leukemia, Myeloid, Acute; Mice; Molecular Sequence Data; Nuclear Proteins; Oncogene Proteins, Fusion; Protein Binding; Protein Interaction Domains and Motifs
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