Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Mazumdar, C; Shen, Y; Xavy, S; Zhao, F; Reinisch, A; Li, R; Corces, MR; Flynn, RA; Buenrostro, JD; Chan, SM; Thomas, D; Koenig, JL; Hong, WJ; Chang, HY; Majeti, R.
Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation.
Cell Stem Cell. 2015; 17(6): 675-688.
Doi: 10.1016/j.stem.2015.09.017
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-authors Med Uni Graz
- Reinisch Andreas
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- Recurrent mutations in cohesin complex proteins have been identified in pre-leukemic hematopoietic stem cells and during the early development of acute myeloid leukemia and other myeloid malignancies. Although cohesins are involved in chromosome separation and DNA damage repair, cohesin complex functions during hematopoiesis and leukemic development are unclear. Here, we show that mutant cohesin proteins block differentiation of human hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo and enforce stem cell programs. These effects are restricted to immature HSPC populations, where cohesin mutants show increased chromatin accessibility and likelihood of transcription factor binding site occupancy by HSPC regulators including ERG, GATA2, and RUNX1, as measured by ATAC-seq and ChIP-seq. Epistasis experiments show that silencing these transcription factors rescues the differentiation block caused by cohesin mutants. Together, these results show that mutant cohesins impair HSPC differentiation by controlling chromatin accessibility and transcription factor activity, possibly contributing to leukemic disease. Copyright © 2015 Elsevier Inc. All rights reserved.
- Find related publications in this database (using NLM MeSH Indexing)
- Cell Cycle Proteins - genetics
- Cell Differentiation -
- Chromatin - metabolism
- Chromosomal Proteins, Non-Histone - genetics
- Core Binding Factor Alpha 2 Subunit - metabolism
- GATA2 Transcription Factor - metabolism
- Gene Expression Regulation, Leukemic -
- Hematopoiesis -
- Hematopoietic Stem Cells - cytology
- Humans -
- Leukemia, Myeloid, Acute - metabolism
- Mutation -
- Stem Cells - cytology
- Transcriptional Regulator ERG - metabolism