Abstract
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.
Highlights
Despite significant advances in leukemia research, the factors that promote the selection and expansion of mutated cells leading to leukemia are not well known
We show that impaired DNA replication of hematopoietic progenitors in E2f1/E2f2 mutant mice or mice treated with hydroxyurea (HU) allows Bcr-Abl-expressing and p53-mutated progenitors to outcompete nonmutated cells in the same niche, promoting leukemogenesis
DNA replication in bone marrow (BM) progenitor cell populations is severely impaired in E2f1À/ÀE2f2À/À (DKO) mice, but not in E2f1þ/ÀE2f2þ/À mice, leading to severe hematopoietic deficiencies [7]
Summary
Despite significant advances in leukemia research, the factors that promote the selection and expansion of mutated cells leading to leukemia are not well known. Acquired mutations contributing to leukemogenesis, including chromosomal translocations that generate oncogenic fusion genes, may need to occur in hematopoietic stem cells (HSCs), as these cells have sufficient lifespan necessary for the acquisition of additional mutagenic hits. Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease characterized by excessive proliferation of progenitor cells with massive accumulation of mature myeloid lineage cells. The CML-associated p210 Bcr-Abl gene is found in myeloid, erythroid, and lymphoid lineage cells in CML patients, suggesting that the translocation originally occurred in a pluripotent stem cell [3]. Recent evidence suggests that while the p210 Bcr-Abl fusion is found in HSC, the leukemia stem cells for both p210- and p190-associated ALLs possess committed B progenitor phenotypes [4]. Bcr-Abl expression increases genomic instability, in part by stimulating homologous recombination repair, which can promote survival after DNA damage, while increasing recombination and loss of heterozygosity events [6]
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