Submitted January 22, 2007
Accepted June 2, 2007
Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia
Robert A.J. Signer, Encarnacion Montecino-Rodriguez, Owen N Witte, Jami McLaughlin, and Kenneth Dorshkind*
Department of Pathology & Laboratory Medicine, & the Hematopoietic Malignancies Program, Jonsson Comprehensive Cancer Ctr, University of California, Los Angeles, CA, United States
Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
* Corresponding author; email: kdorshki{at}mednet.ucla.edu.
Reduced lymphopoiesis during aging contributes to declines in immunity, but little consideration has been given to its effect on the development of hematological 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 (CML), an adult-onset malignancy arising from transformation of hematopoietic stem cells (HSC) by the BCR-ABLP210 oncogene, we demonstrate that young bone marrow (BM) cells transformed with BCR-ABLP210 initiated both a myeloproliferative disorder (MPD) and B lymphoid leukemia while BCR-ABLP210 transformed old BM cells recapitulated the human disease by inducing a MPD with rare lymphoid involvement. Further, the lesser severity of MPDs initiated from old BCR-ABLP210 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.
