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Relative fitness of hematopoietic progenitors influences leukemia progression

Leukemia volume 25, pages 891–895 (2011)Cite this article

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The development of leukemia is a complex, multistep process that is not fully understood. Although many leukemias harbor chromosomal translocations and additional mutations that drive oncogenic transformation, non-genetic factors also contribute to leukemia development. We have demonstrated that the relative fitness of hematopoietic progenitor cells (HPC) has a major role in leukemogenesis.1, 2 That is, the presence of normally functioning HPC can slow or eliminate leukemia development from a small pool of cells harboring an oncogene, whereas the presence of HPC that have impaired fitness enhances leukemogenesis. However, the importance of these findings seems to be underappreciated, perhaps because a clinically relevant model has not yet been demonstrated. We propose that a clinical correlate of our previous work is the development of treatment-related acute myelogenous leukemia (tAML) in patients who are treated with DNA-damaging agents, followed by myelosuppressive agents that impair the relative fitness of HPC.

tAML is one of the most devastating side effects of cancer therapy and occurs in 2–15% of patients treated for cancer.3 Clinical chemotherapeutics that act by inhibition of topoisomerase II (for example, etoposide and daunomycin) are known to induce MLL gene rearrangements associated with tAML. Depending on the treatment protocol, these drugs may be followed by other myelosuppressive drugs (for example, purine antimetabolites such as, 6-mercaptopurine (or historically, 6-thioguanine (6TG)) and/or antifolates such as methotrexate), which have also been associated with tAML.4 Thus, it is possible that leukemia may be initiated by a topoisomerase inhibitor and promoted by subsequent therapy. We hypothesized that the administration of a clinically relevant chemotherapeutic would promote leukemia development from oncogene harboring HPC, in part, by impairing the relative fitness of normal HPC.

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Acknowledgements

This work was supported by grants from the Brent Eley Foundation (CP), the Cancer League of Colorado (CP), The National Institutes of Health (P20 CA103680-CP; RO1 CA109657-JD) and the Leukemia and Lymphoma Society (108692-JD). MLL-AF9+ and HPRTmt mice were kindly provided by Drs JH Kersey and HA Jinnah, respectively.

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Authors and Affiliations

  1. Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA

    C C Porter, D Baturin, R Choudhary & J DeGregori

  2. Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA

    J DeGregori

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  1. C C Porter
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  2. D Baturin
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  3. R Choudhary
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  4. J DeGregori
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Correspondence to C C Porter or J DeGregori.

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Porter, C., Baturin, D., Choudhary, R. et al. Relative fitness of hematopoietic progenitors influences leukemia progression. Leukemia 25, 891–895 (2011). https://doi.org/10.1038/leu.2011.22

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