TY - JOUR
T1 - Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms
AU - Mullenders, Jasper
AU - Aranda-Orgilles, Beatriz
AU - Lhoumaud, Priscillia
AU - Keller, Matthew
AU - Pae, Juhee
AU - Wang, Kun
AU - Kayembe, Clarisse
AU - Rocha, Pedro P.
AU - Raviram, Ramya
AU - Gong, Yixiao
AU - Premsrirut, Prem K.
AU - Tsirigos, Aristotelis
AU - Bonneau, Richard
AU - Skok, Jane A.
AU - Cimmino, Luisa
AU - Hoehn, Daniela
AU - Aifantis, Iannis
N1 - Publisher Copyright:
© 2015 Mullenders et al.
PY - 2015/10/19
Y1 - 2015/10/19
N2 - The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy.
AB - The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy.
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U2 - 10.1084/jem.20151323
DO - 10.1084/jem.20151323
M3 - Article
C2 - 26438359
AN - SCOPUS:84952061852
SN - 0022-1007
VL - 212
SP - 1833
EP - 1850
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
ER -