Towards a better understanding of cohesin mutations in AML

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Title: Towards a better understanding of cohesin mutations in AML
Authors: Cuartero, S
Innes, AJ
Merkenschlager, M
Item Type: Journal Article
Abstract: Classical driver mutations in acute myeloid leukemia (AML) typically affect regulators of cell proliferation, differentiation, and survival. The selective advantage of increased proliferation, improved survival, and reduced differentiation on leukemia progression is immediately obvious. Recent large-scale sequencing efforts have uncovered numerous novel AML-associated mutations. Interestingly, a substantial fraction of the most frequently mutated genes encode general regulators of transcription and chromatin state. Understanding the selective advantage conferred by these mutations remains a major challenge. A striking example are mutations in genes of the cohesin complex, a major regulator of three-dimensional genome organization. Several landmark studies have shown that cohesin mutations perturb the balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data now begin to uncover the molecular mechanisms that underpin this phenotype. Among these mechanisms is a role for cohesin in the control of inflammatory responses in HSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and drive HSPC differentiation. Consistent with this, cohesin mutations promote resistance to inflammatory signals, and may provide a selective advantage for AML progression. In this review, we discuss recent progress in understanding cohesin mutations in AML, and speculate whether vulnerabilities associated with these mutations could be exploited therapeutically
Issue Date: 9-Sep-2019
Date of Acceptance: 21-Aug-2019
URI: http://hdl.handle.net/10044/1/73631
DOI: https://doi.org/10.3389/fonc.2019.00867
ISSN: 2234-943X
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Oncology
Volume: 9
Copyright Statement: © 2019 Cuartero, Innes and Merkenschlager. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
NIHR
Funder's Grant Number: 099276/Z/12/Z
PO4050659629
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
cohesin
leukemia
interferon
inflammation
hematopoiesis
AML
HEMATOPOIETIC STEM-CELLS
SISTER-CHROMATID COHESION
MYELOID-LEUKEMIA CELLS
BONE-MARROW-CELLS
REMODELING COMPLEX
SELF-RENEWAL
EPIGENETIC REGULATORS
PROGENITOR CELLS
GENE-EXPRESSION
KAPPA-B
Science & Technology
Life Sciences & Biomedicine
Oncology
cohesin
leukemia
interferon
inflammation
hematopoiesis
AML
HEMATOPOIETIC STEM-CELLS
SISTER-CHROMATID COHESION
MYELOID-LEUKEMIA CELLS
BONE-MARROW-CELLS
REMODELING COMPLEX
SELF-RENEWAL
EPIGENETIC REGULATORS
PROGENITOR CELLS
GENE-EXPRESSION
KAPPA-B
1112 Oncology and Carcinogenesis
Publication Status: Published
Article Number: 867
Online Publication Date: 2019-09-09
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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