Impaired DNA Replication within Progenitor Cell Pools Promotes Leukemogenesis

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.

Declining lymphoid progenitor fitness promotes aging-associated leukemogenesis

“…Flow cytometric analyses of phosphorylated signaling proteins (37) were as performed previously, with modifications. Additional flow cytometric analyses, retroviral transduction, BMT (omitting 5-fluorouracil priming), and pathological examinations were performed as described by Bilousova et al (13). Statistical analysis was performed using GraphPad Prism 5 software.…”

“…We have previously demonstrated that contexts of reduced cellular fitness caused by replicational stress or combined genetic disruption of E2f1 and E2f2 increase the selective advantage conferred by expression of Bcr-Abl in hematopoietic progenitors and that this increased selective advantage translates into increased leukemogenesis (13). The chromosomal translocation generating p210 Bcr-Abl is the major cause of chronic myelogenous leukemia (CML), and translocations generating p210 or p190 Bcr-Abl fusions are present in acute lymphoblastic leukemias (ALLs) (14).…”

Too much to handle — how gaining chromosomes destabilizes the genome

“…defective replication induced by aphidicolin-mediated DNA polymerase inhibition results in a high frequency of tumor-like micro-deletions; 22 hydroxyurea-induced dNTP depletion resulting in replication stress and DNA damage promotes leukemogenesis in mice. 23 Our findings show that missegregation of even a single chromosome might instigate genomic instability by elevating replication stress, which in turn might contribute to tumorigenesis.…”

“…They demonstrated that conditions that impair DNA replication (in this case mutation of E2F1/E2F2) in haematopoietic progenitors significantly enhanced the proliferative advantage after oncogene expression or p53 mutation, while healthy replicating progenitors cells did not gain any benefit. 23 The competitive advantage allows mutant progenitors cells to outcompete wild type cells in the same niche, promoting leukemogenesis. Thus, in a replication-impaired scenario acquisition of oncogenic mutations might provide a relatively larger selective advantage.…”

“…In contrast, oncogenic mutations are mainly disadvantageous and are usually selected against in the wild type population. 23 While genomic instability of aneuploid cells may on one hand impair proliferation, it provides on the other hand a source of genetic variation, thus allowing cells to adapt under strong selective forces. In yeast strains that are cultured under prolonged stress stimuli, aneuploidy arises as a transient adaptation to allow cells to survive while developing a long-term evolutionarily stable solution.…”