Roles of the histone acetyltransferase monocytic leukemia zinc finger protein in normal and malignant hematopoiesis

Abstract

Histone-modified enzymes are involved in various cell functions, including proliferation, differentiation, cell death and carcinogenesis. The protein MOZ (monocytic leukemia zinc finger protein) is a Myst (MOZ, Ybf2 (Sas3), Sas2, Tip60)-type histone acetyltranseferase (HAT) that generates fusion genes, such as MOZ-TIF2, MOZ-CBP and MOZ-p300, in acute myeloid leukemia (AML) by chromosomal translocation. MOZ associates with AML1 (RUNX1), PU.1, and p53, and cooperatively activates target gene transcription. Gene targeting in mice has revealed that MOZ is essential for the generation and maintenance of hematopoietic stem cells (HSC) and for the appropriate development of myeloid, erythroid and B-lineage cell progenitors. In AML, MOZ fusion genes lead to repressed differentiation, hyper-proliferation, and self-renewal of myeloid progenitors through deregulation of MOZ-regulated target gene expression. It is therefore necessary to analyze the roles of MOZ and MOZ fusion genes in normal and malignant hematopoiesis to elucidate the mechanisms underlying and develop therapies for MOZ-related AML.

Figure 1

Structure of normal monocytic leukemia zinc finger protein (MOZ) and leukemia‐associated MOZ fusion proteins. MOZ has various functional domains including H1/5 (H15; histone H1/H5–like), PHD (plant homeobox–like domain) zinc finger, B basic (b), histone acetyltranseferase (HAT) and acidic domains. S, PQ and M indicate serine‐, proline‐ and glutamine‐, and methionine‐rich domains, respectively. MOZ fusions with four known partners are shown: CBP, p300, TIF2 and the recently identified NCOA3. MOZ fusion partners contained CH1 (cystein/histidine rich domain 1), KIX (kinase‐inducible) domain, Bromodomain (Bromo), CID (CBP interacting domain) and AD (activation domain). The breakpoints in the MOZ gene and its fusion partners are shown as black arrows and blue arrows, respectively.

Figure 2

Role of monocytic zinc finger protein (MOZ) in acute myeloid leukemia (AML)1‐dependent transcription. AML1 acts as both a sequence‐specific transacting factor and a scaffold to intermediate the association of HIPK2 and histone acetyltranseferase (HAT). MOZ functions as coactivator for AML1 and activicates AML1‐mediated transcription.

Figure 3

Schematic for fetal hematopoiesis phenotypes of monocytic zinc finger protein (MOZ)‐deficient mice. The MOZ‐deficient fetal liver contains reduced hematopoietic progenitor and hematopoietic stem cells (HSC) have lost their self‐renewal activity. Levels of CD19⁺ B‐lineage cells and mature erythrocytes are also severely reduced. In contrast, myeloid cell and KLSF (c‐Kit⁺, Lin⁻, Sca‐1⁻, FcRγ⁺) populations are increased in the MOZ‐deficient fetal liver.

Figure 4

Models of aberrant transcription in acute myeloid leukemia (AML) with monocytic leukemia zinc finger protein (MOZ) fusion genes. (a) MOZ maintains appropriate chromatin status to regulate target gene expression and hematopoiesis. (b) Constitutively active transcription is induced by MOZ fusion proteins through unusual chromatin status such as hyper‐acetylation in leukemia. (c) MOZ fusions induce unusual chromatin status and then down‐regulate target gene expression. (d) MOZ fusions deplete transcription factors and/or their coactovators, and then down‐regulate target gene expression. Ac, acetylation.