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Chemotherapy and irradiation cause DNA damage to hematopoietic stem cells (HSCs), leading to HSC depletion and dysfunction and the risk of malignant transformation over time. Extrinsic regulation of HSC DNA repair is not well understood, and therapies to augment HSC DNA repair following myelosuppression remain undeveloped. We report that epidermal growth factor receptor (EGFR) regulates DNA repair in HSCs following irradiation via activation of the DNA-dependent protein kinase-catalytic subunit (DNA-PKcs) and nonhomologous end joining (NHEJ). We show that hematopoietic regeneration in vivo following total body irradiation is dependent upon EGFR-mediated repair of DNA damage via activation of DNA-PKcs. Conditional deletion of EGFR in hematopoietic stem and progenitor cells (HSPCs) significantly decreased DNA-PKcs activity following irradiation, causing increased HSC DNA damage and depressed HSC recovery over time. Systemic administration of epidermal growth factor (EGF) promoted HSC DNA repair and rapid hematologic recovery in chemotherapy-treated mice and had no effect on acute myeloid leukemia growth in vivo. Further, EGF treatment drove the recovery of human HSCs capable of multilineage in vivo repopulation following radiation injury. Whole-genome sequencing analysis revealed no increase in coding region mutations in HSPCs from EGF-treated mice, but increased intergenic copy number variant mutations were detected. These studies demonstrate that EGF promotes HSC DNA repair and hematopoietic regeneration in vivo via augmentation of NHEJ. EGF has therapeutic potential to promote human hematopoietic regeneration, and further studies are warranted to assess long-term hematopoietic effects.

Titel:	Epidermal growth factor receptor-dependent DNA repair promotes murine and human hematopoietic regeneration.
Autor/in / Beteiligte Person:	Fang, T ; Zhang, Y ; Chang, VY ; Roos, M ; Termini, CM ; Signaevskaia, L ; Quarmyne, M ; Lin, PK ; Pang, A ; Kan, J ; Yan, X ; Javier, A ; Pohl, K ; Zhao, L ; Scott, P ; Himburg, HA ; Chute, JP
Zeitschrift:	Blood, Jg. 136 (2020-07-23), Heft 4, S. 441
Veröffentlichung:	2021- : [New York] : Elsevier ; <i>Original Publication</i>: New York, Grune & Stratton [etc.], 2020
Medientyp:	academicJournal
ISSN:	1528-0020 (electronic)
DOI:	10.1182/blood.2020005895
Schlagwort:	Animals Calcium-Binding Proteins genetics Calcium-Binding Proteins metabolism DNA Damage DNA-Activated Protein Kinase genetics DNA-Activated Protein Kinase metabolism DNA-Binding Proteins genetics DNA-Binding Proteins metabolism Epidermal Growth Factor genetics Epidermal Growth Factor metabolism ErbB Receptors genetics Hematopoietic Stem Cells cytology Humans Mice DNA End-Joining Repair ErbB Receptors metabolism Hematopoiesis physiology Hematopoietic Stem Cells metabolism Regeneration
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Blood] 2020 Jul 23; Vol. 136 (4), pp. 441-454. MeSH Terms: DNA End-Joining Repair* ; Regeneration* ; ErbB Receptors / metabolism ; Hematopoiesis / physiology ; Hematopoietic Stem Cells / *metabolism ; Animals ; Calcium-Binding Proteins / genetics ; Calcium-Binding Proteins / metabolism ; DNA Damage ; DNA-Activated Protein Kinase / genetics ; DNA-Activated Protein Kinase / metabolism ; DNA-Binding Proteins / genetics ; DNA-Binding Proteins / metabolism ; Epidermal Growth Factor / genetics ; Epidermal Growth Factor / metabolism ; ErbB Receptors / genetics ; Hematopoietic Stem Cells / cytology ; Humans ; Mice References: PLoS One. 2018 Dec 12;13(12):e0209034. (PMID: 30540841) ; Blood. 2011 Jan 13;117(2):e27-38. (PMID: 20980679) ; Cell Stem Cell. 2013 Jan 3;12(1):37-48. 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(PMID: 25152801) Grant Information: P30 CA016042 United States CA NCI NIH HHS; K08 HL138305 United States HL NHLBI NIH HHS; P50 CA211015 United States CA NCI NIH HHS; U01 AI107333 United States AI NIAID NIH HHS; U19 AI067769 United States AI NIAID NIH HHS Substance Nomenclature: 0 (CIB1 protein, human) ; 0 (Calcium-Binding Proteins) ; 0 (DNA-Binding Proteins) ; 62229-50-9 (Epidermal Growth Factor) ; EC 2.7.10.1 (EGFR protein, human) ; EC 2.7.10.1 (EGFR protein, mouse) ; EC 2.7.10.1 (ErbB Receptors) ; EC 2.7.11.1 (DNA-Activated Protein Kinase) ; EC 2.7.11.1 (Prkdc protein, mouse) Entry Date(s): Date Created: 20200506 Date Completed: 20210225 Latest Revision: 20240214 Update Code: 20240214 PubMed Central ID: PMC7378456

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Epidermal growth factor receptor-dependent DNA repair promotes murine and human hematopoietic regeneration.