Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

J Exp Med. 2015 Oct 19;212(11):1833-50. doi: 10.1084/jem.20151323. Epub 2015 Oct 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Cell Differentiation
  • Chromatin / physiology
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / physiology*
  • Hematopoietic Stem Cells / physiology*
  • Homeostasis*
  • Humans
  • Mice
  • Myeloproliferative Disorders / etiology*
  • Tumor Suppressor Proteins / physiology*

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Tumor Suppressor Proteins
  • cohesins