Declining lymphoid progenitor fitness promotes aging-associated leukemogenesis

Department of Biochemistry and Molecular Genetics and Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2010; 107(50):21713-8. DOI: 10.1073/pnas.1005486107
Source: PubMed


Aging is associated with the functional decline of cells, tissues, and organs. At the same time, age is the single most important prognostic factor in the development of most human cancers, including chronic myelogenous and acute lymphoblastic leukemias initiated by Bcr-Abl oncogenic translocations. Prevailing paradigms attribute the association between aging and cancers to the accumulation of oncogenic mutations over time, because the accrual of oncogenic events is thought to be the rate-limiting step in initiation and progression of cancers. Conversely, aging-associated functional decline caused by both cell-autonomous and non-cell-autonomous mechanisms is likely to reduce the fitness of stem and progenitor cell populations. This reduction in fitness should be conducive for increased selection of oncogenic mutations that can at least partially alleviate fitness defects, thereby promoting the initiation of cancers. We tested this hypothesis using mouse hematopoietic models. Our studies indicate that the dramatic decline in the fitness of aged B-lymphopoiesis coincides with altered receptor-associated kinase signaling. We further show that Bcr-Abl provides a much greater competitive advantage to old B-lymphoid progenitors compared with young progenitors, coinciding with restored kinase signaling pathways, and that this enhanced competitive advantage translates into increased promotion of Bcr-Abl-driven leukemias. Moreover, impairing IL-7-mediated signaling is sufficient to promote selection for Bcr-Abl-expressing B progenitors. These studies support an unappreciated causative link between aging and cancer: increased selection of oncogenic mutations as a result of age-dependent alterations of the fitness landscape.

Download full-text


Available from: James Degregori
  • Source
    • "In summary, normal hepatocyte transplantation is able to delay DENA+RS-induced carcinogenic process and it is also associated with extensive remodeling of the tissue landscape, consisting in the massive replacement of resident senescent hepatocytes with phenotypically normal cells. It is noteworthy that our results are reminiscent of those reported by the group of the DeGregori in the hematopoietic system: it was observed that transplantation of young, normal bone marrow cells was able to prevent the clonal expansion and leukemogenesis mediated by initiated progenitors in the context of an aged or previously irradiated bone marrow microenvironment [38,39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.
    Full-text · Article · Jan 2014 · Aging
  • Source
    • "To assess ERK1/2 phosphorylation using flow cytometry, cells were cultured in 6-well plates at approximately 1x105 per well and treated with either PPIA at 25 μM or buffer for the indicated times. The ERK1/2 phosphorylation assay was quantified by flow cytometry using anti-pERK1/2 (BD Biosciences) performed as we have previously described [55]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although the peptidyl-prolyl isomerase, cyclophilin-A (peptidyl-prolyl isomerase, PPIA), has been studied for decades in the context of its intracellular functions, its extracellular roles as a major contributor to both inflammation and multiple cancers have more recently emerged. A wide range of activities have been ascribed to extracellular PPIA that include induction of cytokine and matrix metalloproteinase (MMP) secretion, which potentially underlie its roles in inflammation and tumorigenesis. However, there have been conflicting reports as to which particular signaling events are under extracellular PPIA regulation, which may be due to either cell-dependent responses and/or the use of commercial preparations recently shown to be highly impure. We have produced and validated the purity of recombinant PPIA in order to subject it to a comparative analysis between different cell types. Specifically, we have used a combination of multiple methods such as luciferase reporter screens, translocation assays, phosphorylation assays, and nuclear magnetic resonance to compare extracellular PPIA activities in several different cell lines that included epithelial and monocytic cells. Our findings have revealed that extracellular PPIA activity is cell type-dependent and that PPIA signals via multiple cellular receptors beyond the single transmembrane receptor previously identified, Extracellular Matrix MetalloPRoteinase Inducer (EMMPRIN). Finally, while our studies provide important insight into the cell-specific responses, they also indicate that there are consistent responses such as nuclear factor kappa B (NFκB) signaling induced in all cell lines tested. We conclude that although extracellular PPIA activates several common pathways, it also targets different receptors in different cell types, resulting in a complex, integrated signaling network that is cell type-specific.
    Full-text · Article · May 2012 · Cancer Cell International
  • Source
    • "Other data indicate that aged HSCs show increased levels of γH2AX staining, a surrogate marker for DNA double strand breaks [23] and that young HSCs might be able to accumulate cytogenetical aberrations over a lifetime as a result of incorrectly repaired DNA damage [24]. In contrast, arguing against solely cell intrinsic mechanisms in age-associated increase in the incidence of leukemia is for example the finding that aged B-lymphoid progenitors allow for a greater competitive advantage of leukemic cells compared to young B-lymphoid progenitors and that this decline in competitiveness of aged B-lymphoid progenitors increased the progression of bcr-abl driven leukemia [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular and cellular mechanisms of the age-associated increase in the incidence of acute myeloid leukemia (AML) remain poorly understood. Multiple studies support that the bone marrow (BM) microenvironment has an important influence on leukemia progression. Given that the BM niche itself undergoes extensive functional changes during lifetime, we hypothesized that one mechanism for the age-associated increase in leukemia incidence might be that an aged niche promotes leukemia progression. The most frequent genetic alteration in AML is the t(8;21) translocation, resulting in the expression of the AML1-ETO fusion protein. Expression of the fusion protein in hematopoietic cells results in mice in a myeloproliferative disorder. Testing the role of the age of the niche on leukemia progression, we performed both transplantation and in vitro co-culture experiments. Aged animals transplanted with AML1-ETO positive HSCs presented with a significant increase in the frequency of AML-ETO positive early progenitor cells in BM as well as an increased immature myeloid cell load in blood compared to young recipients. These findings suggest that an aged BM microenvironment allows a relative better expansion of pre-leukemic stem and immature myeloid cells and thus imply that the aged microenvironment plays a role in the elevated incidence of age-associated leukemia.
    Full-text · Article · Feb 2012 · PLoS ONE
Show more

Similar Publications