Functional consequences of cohesin complex mutations on normal and malignant hematopoiesis

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Recent studies have identified recurrent mutations in all components of the cohesin complex in acute myeloid leukemia and other myeloid malignancies, and, importantly, have shown these mutations to occur early in disease pathogenesis and in pre-leukemic hematopoietic stem cells. Here, we investigate the impact of these mutations on hematopoiesis and demonstrate that introduction of cohesin mutants into normal human hematopoietic stem and progenitor cells (HSPC) results in blocked differentiation and enforcement of stem cell programs both in vitro and in vivo. These effects were cell context dependent, restricted to immature HSPC populations. Cohesin mutants selectively increased chromatin accessibility and likelihood of occupancy at binding sites for transcription factors known to regulate HSPC including ERG, GATA2, and RUNX1 as measured by ATAC-Seq and ChIP-Seq. Furthermore, epistasis experiments showed that silencing of these transcription factors 2in which mutant cohesin impairs hematopoietic differentiation and aberrantly enforces stem cell programs through the modulation of HSPC chromatin accessibility and transcription factor activity.


Type of resource text
Form electronic; electronic resource; remote
Extent 1 online resource.
Publication date 2015
Issuance monographic
Language English


Associated with Mazumdar, Claire
Associated with Stanford University, Department of Cancer Biology.
Primary advisor Majeti, Ravindra, 1972-
Thesis advisor Majeti, Ravindra, 1972-
Thesis advisor Chang, Howard
Thesis advisor Mitchell, Beverly Eileen
Thesis advisor Winslow, Monte
Advisor Chang, Howard
Advisor Mitchell, Beverly Eileen
Advisor Winslow, Monte


Genre Theses

Bibliographic information

Statement of responsibility Claire Mazumdar.
Note Submitted to the Program of Cancer Biology.
Thesis Thesis (Ph.D.)--Stanford University, 2015.
Location electronic resource

Access conditions

© 2015 by Claire Mazumdar
This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).

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