Functional consequences of cohesin complex mutations on normal and malignant hematopoiesis
Abstract/Contents
- Abstract
- 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.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| 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 |
Subjects
| 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
- Copyright
- © 2015 by Claire Mazumdar
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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