TY - JOUR
T1 - Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ-TIF2 fusion
AU - Shima, Haruko
AU - Yamagata, Kazutsune
AU - Aikawa, Yukiko
AU - Shino, Mika
AU - Koseki, Haruhiko
AU - Shimada, Hiroyuki
AU - Kitabayashi, Issay
PY - 2014/1
Y1 - 2014/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s12185-013-1466-x
DO - 10.1007/s12185-013-1466-x
M3 - Article
C2 - 24258712
AN - SCOPUS:84899095665
SN - 0925-5710
VL - 99
SP - 21
EP - 31
JO - International Journal of Hematology
JF - International Journal of Hematology
IS - 1
ER -