Towards a Better Understanding of Cohesin Mutations in AML
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.00867/full |
| _version_ | 1811200971477352448 |
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| author | Sergi Cuartero Sergi Cuartero Sergi Cuartero Andrew J. Innes Andrew J. Innes Matthias Merkenschlager |
| author_facet | Sergi Cuartero Sergi Cuartero Sergi Cuartero Andrew J. Innes Andrew J. Innes Matthias Merkenschlager |
| author_sort | Sergi Cuartero |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:13:44Z |
| format | Article |
| id | doaj.art-c03f2961745a4c0f9f9e33daef0f41d1 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T02:13:44Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c03f2961745a4c0f9f9e33daef0f41d12022-12-22T03:52:19ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-09-01910.3389/fonc.2019.00867462818Towards a Better Understanding of Cohesin Mutations in AMLSergi Cuartero0Sergi Cuartero1Sergi Cuartero2Andrew J. Innes3Andrew J. Innes4Matthias Merkenschlager5Faculty of Medicine, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Imperial College London, London, United KingdomCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC), Barcelona, SpainFaculty of Medicine, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Imperial College London, London, United KingdomFaculty of Medicine, Centre for Haematology, Imperial College London, London, United KingdomFaculty of Medicine, MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Imperial College London, London, United KingdomClassical 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.https://www.frontiersin.org/article/10.3389/fonc.2019.00867/fullcohesinleukemiainterferoninflammationhematopoiesisAML |
| spellingShingle | Sergi Cuartero Sergi Cuartero Sergi Cuartero Andrew J. Innes Andrew J. Innes Matthias Merkenschlager Towards a Better Understanding of Cohesin Mutations in AML Frontiers in Oncology cohesin leukemia interferon inflammation hematopoiesis AML |
| title | Towards a Better Understanding of Cohesin Mutations in AML |
| title_full | Towards a Better Understanding of Cohesin Mutations in AML |
| title_fullStr | Towards a Better Understanding of Cohesin Mutations in AML |
| title_full_unstemmed | Towards a Better Understanding of Cohesin Mutations in AML |
| title_short | Towards a Better Understanding of Cohesin Mutations in AML |
| title_sort | towards a better understanding of cohesin mutations in aml |
| topic | cohesin leukemia interferon inflammation hematopoiesis AML |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.00867/full |
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