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Sensitivity and Resistance to Therapy

SP/drug efflux functionality of hematopoietic progenitors is controlled by mesenchymal niche through VLA-4/CD44 axis

Leukemia volume 28, pages 853–864 (2014)Cite this article

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Abstract

Hematopoiesis is orchestrated by interactions between hematopoietic stem/progenitor cells (HSPCs) and stromal cells within bone marrow (BM) niches. Side population (SP) functionality is a major characteristic of HSPCs related to quiescence and resistance to drugs and environmental stresses. At steady state, SP cells are mainly present in the BM and are mostly absent from the circulation except in stress conditions, raising the hypothesis of the versatility of the SP functionality. However, the mechanism of SP phenotype regulation is unclear. Here we show for the first time that the SP functionality can be induced in lin− cells from unmobilized peripheral blood after nesting on mesenchymal stromal cells (MSCs). This MSC-induced SP fraction contains HSPCs as demonstrated by their (i) CD34+ cell percentage, (ii) quiescent status, (iii) in vitro proliferative and clonogenic potential, (iv) engraftment in NSG (NOD SCID gamma chain) mice and (v) stemness gene expression profile. We demonstrate that SP phenotype acquisition/reactivation by circulating lin− cells is dependent on interactions with MSCs through VLA-4/α4β1-integrin and CD44. A similar integrin-dependent mechanism of SP phenotype acquisition in acute myeloid leukemia circulating blasts suggests an extrinsic regulation of ATP-binding cassette-transporter activity that could be of importance for a better understanding of adhesion-mediated chemoresistance mechanisms.

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Acknowledgements

We are indebted to Dr Massard (Jean Julliard Army Blood Transfusion Center, Clamart, France) and to Dr Konopacki (Service of Hematology, HIA Percy, Clamart, France) for supplying blood and BM samples from healthy donors and AML patients. This work was supported by grants from LNCC (Ligue Nationale Contre le Cancer; No. EL2010.LNCC/MCLBK), Vaincre le Cancer-NRB (Nouvelles Recherches Biomédicales) association, DGA (Délégation Générale pour l’Armement) and Laurette Fugain association (ALF 2013/08).

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  1. J-J Lataillade and M-C Le Bousse-Kerdilès: These authors contributed equally to this work.

Authors and Affiliations

  1. Service d’hématologie, HIA Percy, Clamart, France

    J-V Malfuson & T de Revel

  2. CTS des Armées, Clamart, France

    J-V Malfuson, L Boutin, C Thépenier & J-J Lataillade

  3. Inserm U972, Villejuif, France

    D Clay, C Desterke, F Torossian, B Guerton, A Anginot & M-C Le Bousse-Kerdilès

  4. IFR89, Institut André Lwoff, Villejuif, France

    D Clay & M-C Le Bousse-Kerdilès

  5. Univ Paris-Sud, Villejuif, France

    C Desterke, F Torossian, B Guerton, A Anginot & M-C Le Bousse-Kerdilès

  6. Ecole du Val de Grâce, Paris, France,

    T de Revel & J-J Lataillade

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  1. J-V Malfuson
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Malfuson, JV., Boutin, L., Clay, D. et al. SP/drug efflux functionality of hematopoietic progenitors is controlled by mesenchymal niche through VLA-4/CD44 axis. Leukemia 28, 853–864 (2014). https://doi.org/10.1038/leu.2013.256

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