title: BCL2A1a over-expression in murine hematopoietic stem and progenitor cells decreases apoptosis and results in hematopoietic transformation.
abstract: We previously reported the development of a lethal myeloid sarcoma in a non-human primate model utilizing retroviral vectors to genetically modify hematopoietic stem and progenitor cells. This leukemia was characterized by insertion of the vector provirus into the BCL2A1 gene, with resultant BCL2A1 over-expression. There is little information on the role of this anti-apoptotic member of the BCL2 family in hematopoiesis or leukemia induction. Therefore we studied the impact of Bcl2a1a lentiviral over-expression on murine hematopoietic stem and progenitor cells. We demonstrated the anti-apoptotic function of this protein in hematopoietic cells, but did not detect any impact of Bcl2a1a on in vitro cell growth or cell cycle kinetics. In vivo, we showed a higher propensity of HSCs over-expressing Bcl2a1a to engraft and contribute to hematopoiesis. Mice over-expressing Bcl2a1a in the hematologic compartment eventually developed an aggressive malignant disease characterized as a leukemia/lymphoma of B-cell origin. Secondary transplants carried out to investigate the primitive origin of the disease revealed the leukemia was transplantable. Thus, Bcl2a1 should be considered as a proto-oncogene with a potential role in both lymphoid and myeloid leukemogenesis, and a concerning site for insertional activation by integrating retroviral vectors utilized in hematopoietic stem cell gene therapy.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Métais
authors.forename: Thomas
authors.initials: T
authors.lastname: Winkler
authors.forename: Julia T
authors.initials: JT
authors.lastname: Geyer
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.forename: Peter D
authors.initials: PD
authors.lastname: Aplan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eckhaus
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000235:genetics
chemical_list: C096816:BCL2-related protein A1; C000715470:MAS1 protein, human; D015778:Minor Histocompatibility Antigens; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2