Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ–TIF2 fusion

• Published in: International journal of hematology 2014, Vol.99 (1), p.21-31
• Main Authors: Shima, Haruko, Yamagata, Kazutsune, Aikawa, Yukiko, Shino, Mika, Koseki, Haruhiko, Shimada, Hiroyuki, Kitabayashi, Issay
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Animals; Biological and medical sciences; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Disease Models, Animal; Gene Expression; Gene Knockdown Techniques; Hematologic and hematopoietic diseases; Hematology; Histone Acetyltransferases - chemistry; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Leukemia - genetics; Leukemia - metabolism; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Molecular Sequence Data; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncology; Original Article; Protein Binding; Protein Interaction Domains and Motifs
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-013-1466-x

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.