STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia.

Autor:	Fischer A; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany; Leibniz Institute for Immunotherapy, Regensburg, Germany., Hernández-Rodríguez B; Regulatory Genomics, Max Plank Institute for Molecular Medicine, Münster, Germany., Mulet-Lazaro R; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Nuetzel M; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany., Hölzl F; Leibniz Institute for Immunotherapy, Regensburg, Germany., van Herk S; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Kavelaars FG; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Stanewsky H; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany., Ackermann U; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany., Niang AH; Regulatory Genomics, Max Plank Institute for Molecular Medicine, Münster, Germany., Diaz N; Regulatory Genomics, Max Plank Institute for Molecular Medicine, Münster, Germany., Reuschel E; Department of Obstetrics and Gynecology, Hospital St. Hedwig of the Order of St. John, Regensburg, Germany., Strieder N; Leibniz Institute for Immunotherapy, Regensburg, Germany., Hernández-López I; Leibniz Institute for Immunotherapy, Regensburg, Germany., Valk PJM; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Vaquerizas JM; Regulatory Genomics, Max Plank Institute for Molecular Medicine, Münster, Germany; Department of Developmental Epigenomics, MRC London Institute of Medical Sciences, London, UK; Institute of Clinical Sciences, Imperial College London, London, UK., Rehli M; Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany; Leibniz Institute for Immunotherapy, Regensburg, Germany., Delwel R; Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands., Gebhard C; Leibniz Institute for Immunotherapy, Regensburg, Germany. Electronic address: claudia.gebhard@klinik.uni-regensburg.de.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Aug 27; Vol. 43 (8), pp. 114498. Date of Electronic Publication: 2024 Jul 30.
DOI:	10.1016/j.celrep.2024.114498
Abstrakt:	Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2, but not its paralog STAG1, are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression, and local chromatin activation, which were not compensated by the remaining STAG1-cohesin. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. Complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs) revealed effects resembling STAG2-mutant AML-specific changes following STAG2 knockdown, not invoked by the depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression, and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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