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Chronic Lymphocytic Leukemia

B-chronic lymphocytic leukemia chemoresistance involves innate and acquired leukemic side population cells

Leukemia volume 24, pages 1885–1892 (2010)Cite this article

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Abstract

B-cell chronic lymphocytic leukemia (B-CLL) therapy remains unsatisfactory due to repeated resurgences of the chemoresistant disease. In this study, we investigated the basis of this chemoresistance by applying the ‘side population’ (SP) analysis to blood samples from B-CLL patients. We report the existence of few natural SP cells, which harbors phenotypic and cytogenetic hallmarks of B-CLL in most patients with this disease (n=22). SP cells appeared resistant to conventional B-CLL treatments, such as Fludarabine, Bendamustin or Rituximab. Indeed, treatment with Fludarabine (16/18 cases) or Bendamustin (5/7 cases) resulted in complete elimination of non-SP, whereas cells displaying the SP phenotype were the only surviving. Although some B-CLL SP cells were innately chemoresistant, chemotherapy by Fludarabine selected not only innate SP cells but also induced some acquired SP cells, which arose from non-SP by drug-driven evolution. This SP selection by chemotherapeutic treatments is further supported by the overall increase of the SP percentage in patients who experienced chemotherapy in the preceding year. Functionally, proliferative stimulation of SP cells was able to partially replenish in vitro the non-SP cell compartment of the B-CLL disease. The chemoresistance of B-CLL relies, in our model, on the cellular heterogeneity of B-CLL SP cells and on their regenerating dynamics.

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Acknowledgements

We are grateful to the patients who participated in the study and their referring physicians. We thank Amandine Blanc, Emilie-Fleur Gautier, Catherine Trichard, Emilie Laprévotte, Cyril Broccardo, Julien Familiades and the cytometry platform of IFR150-BMT (Toulouse, France) for helpful discussion and technical assistance. Acknowledgements are also made to Cécile Demur and HIMIP (Hémopathies Inserm Midi-Pyrénées) for cellular banking. EG and AQM designed, performed research, analyzed, interpreted data and wrote the article. F-E L′F-O designed research and collected data. MB and SS performed research, analyzed and interpreted data. LY provided patient's samples. SK analyzed and interpreted data. JJF analyzed and interpreted data and wrote the article. GL designed research and wrote the article. This study was supported by grants from INSERM and Association Laurette Fugain (ALF/ N° 07–05). Emilie Gross is a recipient of a grant from le Ministère délégué à l’Enseignement Supérieur et à la Recherche and la Fondation pour la Recherche Médicale. Samar Kheirallah is a recipient of a grant from le Ministère délégué à l’Enseignement Supérieur et à la Recherche and l’Association pour la Recherche sur le Cancer.

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Authors and Affiliations

  1. INSERM, U563, Toulouse, F-31300 France and Université Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, F-31300, France

    E Gross, L Ysebaert, M Brassac, S Kheirallah, J-J Fournié, G Laurent & A Quillet-Mary

  2. IFR150-BMT, Toulouse, F-31300, France

    F-E L’Faqihi-Olive

  3. CHU Toulouse, Hôpital Purpan, Service d'Hématologie, Toulouse, F-31300, France

    L Ysebaert & G Laurent

  4. CHU Toulouse, Hôpital Purpan, Laboratoire d'Hématologie, Toulouse, F-31300, France

    S Struski

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Correspondence to A Quillet-Mary.

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Gross, E., L’Faqihi-Olive, FE., Ysebaert, L. et al. B-chronic lymphocytic leukemia chemoresistance involves innate and acquired leukemic side population cells. Leukemia 24, 1885–1892 (2010). https://doi.org/10.1038/leu.2010.176

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