Impaired DNA replication within progenitor cell pools promotes leukemogenesis.
Impaired cell cycle progression can be paradoxically associated with increased rates of malignancies. Using retroviral transduction of bone marrow progenitors followed by transplantation into mice, we demonstrate that inhibition of hematopoietic progenitor cell proliferation impairs competition, promoting the expansion of progenitors that acquire oncogenic mutations which restore cell cycle progression. Conditions that impair DNA replication dramatically enhance the proliferative advantage provided by the expression of Bcr-Abl or mutant p53, which provide no apparent competitive advantage under conditions of healthy replication. Furthermore, for the Bcr-Abl oncogene the competitive advantage in contexts of impaired DNA replication dramatically increases leukemogenesis. Impaired replication within hematopoietic progenitor cell pools can select for oncogenic events and thereby promote leukemia, demonstrating the importance of replicative competence in the prevention of tumorigenesis. The demonstration that replication-impaired, poorly competitive progenitor cell pools can promote tumorigenesis provides a new rationale for links between tumorigenesis and common human conditions of impaired DNA replication such as dietary folate deficiency, chemotherapeutics targeting dNTP synthesis, and polymorphisms in genes important for DNA metabolism.
Bilousova
Ganna
G
Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Aurora, Colorado, USA.
Marusyk
Andriy
A
Porter
Christopher C
CC
Cardiff
Robert D
RD
DeGregori
James
J
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006918:Hydroxyurea / Q000494:pharmacology; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse; D016159:Tumor Suppressor Protein p53; D004247:DNA; D016044:Fusion Proteins, bcr-abl; D006918:Hydroxyurea