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CLL

Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to fludarabine

Leukemia volume 18, pages 1934–1940 (2004)Cite this article

Abstract

B cell chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the Western hemisphere, yet many biological and molecular features of the disease remain undefined. CLL cells generate increased levels of radical species such as superoxide and nitric oxide (NO), which is associated with mitochondrial DNA mutations. Considering that NO levels can affect mitochondrial biogenesis, we hypothesized that the inherent nitrosative stress in CLL cells may lead to hyperactive mitochondrial biogenesis. Here we report that primary CLL cells contained significantly more mitochondria than normal lymphocytes and that their mitochondrial mass was significantly related to endogenous NO levels. Expression of the mitochondrial biogenesis factors nuclear respiratory factor-1 and mitochondrial transcription factor A was elevated in most CLL specimens examined and appeared to be related to cellular NO levels. Treatment of B cells with exogenous NO caused a substantial increase in mitochondrial mass. In vitro sensitivity of CLL cells to fludarabine was highly related to mitochondrial mass in that cells with greater mitochondrial mass were less sensitive to the drug. Taken together, our results suggest that NO is a key mediator of mitochondrial biogenesis in CLL and that modulation of mitochondrial biogenesis by NO may alter cellular sensitivity to fludarabine.

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Acknowledgements

This study was supported in part by Grants CA85563, CA100428, CA81534, CA100632 and CA16672 from the National Cancer Institute, the National Institutes of Health, and by fellowships from the American Legion Auxiliary (for JSC and STN).

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Authors and Affiliations

  1. Department of Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    J S Carew, R H Xu & P Huang

  2. Department of Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    S T Nawrocki, K Dunner Jr & D J McConkey

  3. Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    W G Wierda & M J Keating

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  1. J S Carew
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  2. S T Nawrocki
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Correspondence to P Huang.

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Carew, J., Nawrocki, S., Xu, R. et al. Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to fludarabine. Leukemia 18, 1934–1940 (2004). https://doi.org/10.1038/sj.leu.2403545

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