| Autor: |
Fisher, J B, Peterson, J, Reimer, M, Stelloh, C, Pulakanti, K, Gerbec, Z J, Abel, A M, Strouse, J M, Strouse, C, McNulty, M, Malarkannan, S, Crispino, J D, Milanovich, S, Rao, S |
| Zdroj: |
Leukemia; March 2017, Vol. 31 Issue: 3 p712-719, 8p |
| Abstrakt: |
Acute myelogenous leukemia (AML) is a high-risk hematopoietic malignancy caused by a variety of mutations, including genes encoding the cohesin complex. Recent studies have demonstrated that reduction in cohesin complex levels leads to enhanced self-renewal in hematopoietic stem and progenitors (HSPCs). We sought to delineate the molecular mechanisms by which cohesin mutations promote enhanced HSPC self-renewal as this represents a critical initial step during leukemic transformation. We verified that RNAi against the cohesin subunit Rad21causes enhanced self-renewal of HSPCs in vitrothrough derepression of polycomb repressive complex 2 (PRC2) target genes, including Hoxa7and Hoxa9. Importantly, knockdown of either Hoxa7or Hoxa9suppressed self-renewal, implying that both are critical downstream effectors of reduced cohesin levels. We further demonstrate that the cohesin and PRC2 complexes interact and are bound in close proximity to Hoxa7and Hoxa9. Rad21depletion resulted in decreased levels of H3K27me3 at the Hoxa7and Hoxa9promoters, consistent with Rad21 being critical to proper gene silencing by recruiting the PRC2 complex. Our data demonstrates that the cohesin complex regulates PRC2 targeting to silence Hoxa7and Hoxa9and negatively regulate self-renewal. Our studies identify a novel epigenetic mechanism underlying leukemogenesis in AML patients with cohesin mutations. |
| Databáze: |
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