title: Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice.
abstract: Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2-/-mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2-/-mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2-/-Trp53+/-mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells.
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR.
authors.forename: Qing-Shuo
authors.identifier: 0000-0002-4407-6053
authors.initials: QS
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Tang
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR.
authors.forename: Matthew
authors.initials: M
authors.lastname: Deater
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR.
authors.forename: Ngoc
authors.initials: N
authors.lastname: Phan
authors.affiliation: Department of Pathology, Baylor College of Medicine, TX.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Marcogliese
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR.
authors.forename: Muhsen
authors.initials: M
authors.lastname: Al-Dhalimy
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, TX; and.
authors.forename: Angela
authors.initials: A
authors.lastname: Major
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR.
authors.forename: Susan
authors.initials: S
authors.lastname: Olson
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA.|Department of Genome Sciences, University of Washington, Seattle, WA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Monnat
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR.
authors.forename: Markus
authors.identifier: 0000-0002-6616-4345
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D019457:Chromosome Breakage; D004249:DNA Damage; D004032:Diet; D005199:Fanconi Anemia / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology
chemical_list: D000447:Aldehydes; D052236:Fanconi Anemia Complementation Group D2 Protein; D006146:Guanidines; D008687:Metformin; D011070:Poly I-C; C004479:pimagedine