Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia

Department of Pathology and Laboratory Medicine and Hematopoietic Malignancies Program, Jonsson Comprehensive Cancer Center, Los Angels, CA 90095, USA.
Blood (Impact Factor: 10.45). 10/2007; 110(6):1831-9. DOI: 10.1182/blood-2007-01-069401
Source: PubMed

ABSTRACT Reduced lymphopoiesis during aging contributes to declines in immunity, but little consideration has been given to its effect on the development of hematologic disease. This report demonstrates that age-related defects in lymphopoiesis underlie the myeloid dominance of adult leukemia. Using a murine model of chronic myeloid leukemia, an adult-onset malignancy that arises from transformation of hematopoietic stem cells by the BCR-ABL(P210) oncogene, we demonstrate that young bone marrow (BM) cells that were transformed with BCR-ABL(P210) initiated both a myeloproliferative disorder (MPD) and B-lymphoid leukemia, whereas BCR-ABL(P210)-transformed old BM cells recapitulated the human disease by inducing an MPD with rare lymphoid involvement. In addition, the lesser severity of MPDs initiated from old BCR-ABL(P210)-transduced BM cells revealed unappreciated defects in aged myeloid progenitors. These data demonstrate that aging affects patterns of leukemogenesis and indicate that the effects of senescence on hematopoiesis are more extensive than previously appreciated.

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Available from: Encarnacion Montecino-Rodriguez, Sep 25, 2014
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    • "HSCs as pathophysiological determinants in aging Age-related changes in HSCs may be responsible for multiple pathological conditions in the elderly population (Rothstein 2003; Signer et al. 2007). The decline of the lymphoid cell production leads to impaired immune defense and higher susceptibility to infections. "
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    ABSTRACT: Aging is accompanied by reduced regenerative capacity of all tissues and organs and dysfunction of adult stem cells. Notably, these age-related alterations contribute to distinct pathophysiological characteristics depending on the tissue of origin and function and thus require special attention in a type by type manner. In this paper, we review the current understanding of the mechanisms leading to tissue-specific adult stem cell dysfunction and reduced regenerative capacity with age. A comprehensive investigation of the hematopoietic, the neural, the mesenchymal, and the skeletal stem cells in age-related research highlights that distinct mechanisms are associated with the different types of tissue stem cells. The link between age-related stem cell dysfunction and human pathologies is discussed along with the challenges and the future perspectives in stem cell-based therapies in age-related diseases.
    Biogerontology 10/2013; 14(6). DOI:10.1007/s10522-013-9469-9 · 3.29 Impact Factor
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    • "In the hematopoietic system, aging is driven by both intrinsic and extrinsic factors (Chambers and Goodell, 2007; Dorshkind and Swain, 2009; Geiger et al., 2005; Geiger and Van Zant, 2002; Ju et al., 2007; Morrison et al., 1996; Rando, 2006; Rossi et al., 2005) and manifests as decreased immune response (Linton and Dorshkind, 2004), increased myelogenous disease (Kiss et al., 2007; Signer et al., 2007), late-onset anemia (Beghe et al., 2004) and reduced regenerative capacity (Ergen and Goodell, 2009). Multiple studies and our own data demonstrate that the aged murine hematopoietic system is impaired in supporting peripheral blood (PB) leukocyte numbers (Figure S1A), erythropoiesis (Figure S1B–C), B-lymphoid and T-lymphoid cells (Figure S1D), while the number of myeloid cells is increased (Figure S1D). "
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    • "Recent analyses shed some light on the likely contribution of hematopoietic cell intrinsic factors to age-associated leukemia [21]. Signer et al. for example showed that age-associated HSC intrinsic skewing towards myelopoiesis might play a causative role for the myeloid dominance of leukemias in elderly [22]. 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]. "
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    PLoS ONE 02/2012; 7(2):e31523. DOI:10.1371/journal.pone.0031523 · 3.23 Impact Factor
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