Article

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: 9.78). 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.

0 Bookmarks
 · 
76 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aging of stem cells might be the underlying cause of tissue aging in tissue that in the adult heavily rely on stem cell activity, like the blood forming system. Hematopoiesis, the generation of blood forming cells, is sustained by hematopoietic stem cells. In this review article, we introduce the canonical set of phenotypes associated with aged HSCs, focus on the novel aging-associated phenotype apolarity caused by elevated activity of the small RhoGTPase in aged HSCs, disuccs the role of Cdc42 in hematopoiesis and describe that pharmacological inhibition of Cdc42 activity in aged HSCs results in functionally young and thus rejuvenated HSCs.
    Experimental Cell Research 09/2014; 329(2). DOI:10.1016/j.yexcr.2014.09.001 · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aging is organized in a hierarchy, in which aging of cells results in aged tissues, ultimately limiting lifespan. For organ systems that also in the adult depend on stem cells for tissue homeostasis like the hematopoietic system that forms immune cells, it is believed that aging of the stem cells strongly contributes to aging-associated dysfunction. In this review, we summarize current aspects on cellular and molecular mechanisms that are associated with aging of hematopoietic stem cells, the role of the stem cell niche for stem cell aging as well as novel and encouraging experimental approaches to attenuate aging of hematopoietic stem cells to target immunosenescence.
    Current Opinion in Immunology 06/2014; 29C:86-92. DOI:10.1016/j.coi.2014.05.002 · 7.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is well known that cancer is one of the main causes of mortality in the aged population. Recent studies suggest that oncogenic pathways, such as the insulin-like growth factor-1 (IGF-I), Ras, and Akt/PKB, can contribute to both aging and cancer not only by promoting growth and preventing apoptosis, but also by promoting DNA damage and genomic instability. Epidemiological studies suggest that the chronic, low-grade inflammation that accompanies aging also contributes to tissue damage and tumor progression. Coupled with the accumulation of senescent cells and declining immune function, this leads to the generation and survival of cancer cells, possibly explaining why advanced age is the primary risk factor for cancer.
    Critical reviews in oncogenesis 01/2013; 18(6):559-71. DOI:10.1615/CritRevOncog.2013010596

Full-text (2 Sources)

Download
14 Downloads
Available from
Sep 25, 2014