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

• Published in: The Journal of experimental medicine Vol. 212; no. 11; pp. 1819 - 1832
• Main Authors: Viny, Aaron D, Ott, Christopher J, Spitzer, Barbara, Rivas, Martin, Meydan, Cem, Papalexi, Efthymia, Yelin, Dana, Shank, Kaitlyn, Reyes, Jaime, Chiu, April, Romin, Yevgeniy, Boyko, Vitaly, Thota, Swapna, Maciejewski, Jaroslaw P, Melnick, Ari, Bradner, James E, Levine, Ross L
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 19.10.2015
• Subjects: Animals; Brief Definitive Report; Cell Cycle Proteins - genetics; Cell Cycle Proteins - physiology; Chondroitin Sulfate Proteoglycans - genetics; Chromatin - chemistry; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - physiology; Cohesins; fms-Like Tyrosine Kinase 3 - genetics; Haploinsufficiency; Hematopoiesis; Hematopoietic Stem Cells - physiology; Leukemia, Myeloid, Acute - etiology; Leukemia, Myeloid, Acute - genetics; Mice; STAT5 Transcription Factor - physiology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20151317

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 of Smc3 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, Smc3 haploinsufficiency 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.