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Chronic lymphocytic leukemia

Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood

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Abstract

Chronic lymphocytic leukemia (CLL) is a progressive malignancy of mature B-cells that involves the peripheral blood (PB), lymph nodes (LNs) and bone marrow (BM). Although the majority of CLL cells are in a resting state, small populations of proliferating cells exist; however, the anatomical site of active cell proliferation remains to be definitively determined. Based on findings that CLL cells in LNs have increased expression of B-cell activation genes, we tested the hypothesis that the fraction of ‘newly born’ cells would be highest in the LNs. Using a deuterium oxide (2H) in vivo labeling method in which patients consumed deuterated (heavy) water (2H2O), we determined CLL cell kinetics in concurrently obtained samples from LN, PB and BM. The LN was identified as the anatomical site harboring the largest fraction of newly born cells, compared to PB and BM. In fact, the calculated birth rate in the LN reached as high a 3.3% of the clone per day. Subdivision of the bulk CLL population by flow cytometry identified the subpopulation with the CXCR4dimCD5bright phenotype as containing the highest proportion of newly born cells within each compartment, including the LN, identifying this subclonal population as an important target for novel treatment approaches.

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Acknowledgements

We are grateful to all patients who participated in this study. We thank Ajunae Wells for assistance in the clinic, the NIH Surgery Branch, Judy Starling of the NIH Clinical Center Pharmacy and Theresa Davies-Hill for preparing LN single-cell suspensions. In addition, we thank Keyvan Keyvanfar for assistance with flow cytometry. This work was supported by the Intramural Research Program of the National, Heart, Lung and Blood Institute and the National Cancer Institute, the National Institutes of Health and an RO1 grant from the National Cancer Institute, NIH to NC. CUN was supported by the Danish Cancer Society. This research was supported by the Intramural Research Program of the National, Heart, Lung and Blood Institute and the National Cancer Institute. CUN received support from the Danish Cancer Society. Research support was also provided by an RO1 grant from the NIH National Cancer Institute (CA081554) to NC.

Author contributions

Designed the study: TMH, S-SC, NS, CE, XT, TEH, NC, AW; cared for patients: TMH, JV, TEH, GEM, GA, SS, MF, AW; collected data: TMH, S-SC, NS, JV, CE, SS, DCA, MS-S, CMY, CUN, SEMH, NC, AW; analyzed data: TMH, S-SC, NS, CE, MG, XT, DCA, MS-S, CMY, CUN, NC, AW; wrote manuscript: TMH, S-SC, CE, NC, AW.

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Author notes

  1. T M Herndon and S-S Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    T M Herndon, N S Saba, J Valdez, C Sun, C U Niemann, G E Marti, G Aue, S Soto, M Z H Farooqui, S E M Herman & A Wiestner

  2. Department of Medicine, Uniformed Services University, Bethesda, MD, USA

    T M Herndon

  3. The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA

    S-S Chen & N Chiorazzi

  4. KineMed Inc.,, Emeryville, CA, USA

    C Emson & M Gatmaitan

  5. Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    X Tian

  6. Department of Pharmacy, National Institutes of Health Clinical Center, Bethesda, MD, USA

    T E Hughes

  7. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    D C Arthur, M Stetler-Stevenson & C M Yuan

  8. Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA

    N Chiorazzi

  9. Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY, USA

    N Chiorazzi

Authors
  1. T M Herndon
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  2. S-S Chen
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  3. N S Saba
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  4. J Valdez
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  5. C Emson
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  6. M Gatmaitan
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  7. X Tian
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  8. T E Hughes
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  9. C Sun
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  10. D C Arthur
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  11. M Stetler-Stevenson
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  12. C M Yuan
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  13. C U Niemann
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  14. G E Marti
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  15. G Aue
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  16. S Soto
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  17. M Z H Farooqui
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  18. S E M Herman
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  19. N Chiorazzi
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  20. A Wiestner
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Corresponding authors

Correspondence to N Chiorazzi or A Wiestner.

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Competing interests

CE and MG are employees of KineMed Inc. CUN reports consultancy for Roche, Janssen, Gilead, and receipt of travel grants from Roche, Gilead and Novartis. The remaining authors declare no competing financial interests.

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Herndon, T., Chen, SS., Saba, N. et al. Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood. Leukemia 31, 1340–1347 (2017). https://doi.org/10.1038/leu.2017.11

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  • DOI: https://doi.org/10.1038/leu.2017.11

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