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

Haruko Shima, Kazutsune Yamagata, Yukiko Aikawa, Mika Shino, Haruhiko Koseki, Hiroyuki Shimada, Issay Kitabayashi

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)21-31
Number of pages11
JournalInternational journal of hematology
Volume99
Issue number1
DOIs
Publication statusPublished - 2014 Jan

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Keywords

  • AML
  • BRPF1
  • HOX genes
  • MOZ-TIF2

ASJC Scopus subject areas

  • Hematology

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