Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

Abstract: Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences ofSmc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function. Link to article.

Aaron D. Viny,1,2, *Christopher J. Ott,6,7, *Barbara Spitzer,1 Martin Rivas, 8 Cem Meydan, 8 Efthymia Papalexi, 1 Dana Yelin,1, 9 Kaitlyn Shank, 1 Jaime Reyes,6 April Chiu, 3 Yevgeniy Romin, 4 Vitaly Boyko, 4 Swapna Thota,10 Jaroslaw P. Maciejewski, 10 Ari Melnick, 8 James E. Bradner,6,7,** and Ross L. Levine1 ,2,5,**

Submitted: 16 August 2015 | Accepted: 4 September 2015