TitleDose-dependent role of the cohesin complex in normal and malignant hematopoiesis.
Publication TypeJournal Article
Year of Publication2015
AuthorsViny, Aaron D., Ott Christopher J., Spitzer Barbara, Rivas Martín, 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., and Levine Ross L.
JournalJ Exp Med
Date Published2015 Oct 19
KeywordsAnimals, Cell Cycle Proteins, Chondroitin Sulfate Proteoglycans, Chromatin, Chromosomal Proteins, Non-Histone, fms-Like Tyrosine Kinase 3, Haploinsufficiency, Hematopoiesis, Hematopoietic Stem Cells, Leukemia, Myeloid, Acute, Mice, STAT5 Transcription Factor

<p>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.</p>

Alternate JournalJ Exp Med
PubMed ID26438361
PubMed Central IDPMC4612085
Grant ListR01 CA173636 / CA / NCI NIH HHS / United States
K99CA190861 / CA / NCI NIH HHS / United States
T32 CA009512 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K99 CA190861 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States