CHAF1B Suppresses Myeloid Differentiation to Promote Leukemogenesis Free

CHAF1B is a subunit of the heterotrimeric chromatin assembly factor 1 (CAF1) complex, which facilitates the assembly of histone H3.1/H4 heterodimers at the replication fork during S phase. CHAF1B is overexpressed in a variety of cancers including leukemia, but its role in malignancy remains poorly understood, prompting Volk and colleagues to investigate its function in normal and malignant hematopoiesis. Chaf1b was required for normal hematopoiesis, and its deletion in mice resulted in death due to a near-complete loss of hematopoietic cells. Heterozygous expression of Chaf1b was sufficient for viability and normal hematopoiesis. Conversely, overexpression of CHAF1B increased the proliferation of hematopoietic stem and progenitor cells (HSPC) in vitro, and enhanced leukemogenesis in a mouse model of MLL–AF9-driven acute myeloid leukemia (AML). Depleting CHAF1B induced differentiation of MLL–AF9 leukemia cells and suppressed leukemogenesis in vivo. Chromatin immunoprecipitation sequencing showed that CHAF1B occupied discrete regions of chromatin, which were not co-occupied by the DNA replication complex. Instead, CHAF1B blocked chromatin binding by transcription factors that induce myeloid differentiation including CEBPE, CEBPA, FLI1, RUNX1, and RUNX2, thereby blocking differentiation in leukemic cells. This effect required the replication-dependent nucleosome assembly function of CHAF1B, and CHAF1B deletion mutants lacking domains required for replication-dependent nucleosome assembly could not rescue the effects of CHAF1B deletion, suggesting that the canonical replication-linked nucleosome assembly function is required to recruit CHAF1B to chromatin. These findings suggest the potential for therapeutic targeting of CHAF1B, and heterozygous deletion suppressed leukemogenesis in vivo without impairing hematopoietic tissues. A CAF1 dominant negative allele, which binds to CHAF1B to prevent its interaction with PCNA and the replication fork, suppressed leukemogenesis and extended survival in mice with MLL–AF9-driven AML. In addition to elucidating a mechanism by which CHAF1B suppresses myeloid differentiation to promote leukemogenesis, these data suggest that CHAF1B may be a potential therapeutic target in patients with AML.

Volk A, Liang K, Suraneni P, Li X, Zhao J, Bulic M, et al. A CHAF1B-dependent molecular switch in hematopoiesis and leukemia pathogenesis. Cancer Cell 2018;34:707–23.

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