The chromatin-associated Sin3B protein is required for hematopoietic stem cell functions in mice

Abstract

Key Points Inactivation of Sin3B in the hematopoietic compartment impairs HSC functions. Sin3B regulates HSC differentiation and quiescence.

The potential of targeting Sin3B and its associated complexes for cancer therapy

“…Recently, we identified a critical role for Sin3B in maintaining quiescence of hematopoietic stem cells (HSCs) [63]. Similar to observations made in somatic cells, Sin3B loss resulted in the upregulation of E2F target genes in HSCs.…”

“…Additionally, while Sin3B expression levels are not significantly different between healthy individuals and patients affected by blood malignancies, increased Sin3B levels are predictive of a poor prognosis in acute myeloid leukemia (AML; discussed below) [62]. The bases for such effects are currently unknown, but may be related to Sin3B’s ability to regulate HSC differentiation and quiescence [63]. The fact that the expression levels of Sin3B or its associated partners may be either increased or decreased depending on malignancy type likely reflects the wide range of Sin3B targets and its organ-specific biological functions.…”

“…Similar to observations made in somatic cells, Sin3B loss resulted in the upregulation of E2F target genes in HSCs. Moreover, we found that Sin3B associated with E2F4, KDM5A, and HDAC1 in the HSC-like HPC-7 cell line suggesting that Sin3B complexes that regulate cell cycle exit in somatic cells likely mediate similar effects in HSCs [63]. Factors that have been reported to be required for HSC quiescence are often required for leukemic stem cell (LSC) quiescence, and approaches that target LSC quiescence have been successful at eliminating LSCs in mouse models of AML and have been used in patients [99,106].…”

“…For example, while broad HDAC inhibition is effective at eliminating LSCs in a mouse model of chronic myeloid leukemia, it similarly impacts normal HSCs, limiting its efficacy [107,108]. We found that Sin3B loss only mildly perturbs steady-state hematopoiesis [63]. This suggests that a therapeutic window may exist for Sin3B inhibition in AML patients.…”

Zebrafish sin3b mutants are viable but have size, skeletal, and locomotor defects

“…Under serum starvation, MEFs derived from Sin3b knockout mice fail to arrest at G 0 /G 1 and progress further into the cell cycle, but are unable to divide (David et al, ). Disruption of Sin3b in hematopoietic stem cells impedes differentiation (Cantor and David, ). Tissue specific ablation of Sin3b in muscle does not affect survival, but enhances phenotypes produced by disruption of Sin3a (van Oevelen et al, ).…”