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Critical features of FAK-expressing AML bone marrow microenvironment through leukemia stem cell hijacking of mesenchymal stromal cells

Leukemia volume 25, pages 1789–1793 (2011)Cite this article

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The hematopoietic niche is defined as the microenvironment that supports hematopoietic stem cells (HSCs) and is composed of cells that are of mesenchymal origin. The ability of bone marrow (BM) mesenchymal stromal cells (MSCs) to organize the niche results from HSCs/BM MSCs dialogue,1 resulting in an osteoblastic niche that enhances quiescence and resistance of HSCs, and a vascular niche where they could proliferate, differentiate and emigrate in the peripheral blood. In the vascular niche, MSCs may acquire the CD146-expressing and CXCL-12 abundant reticular cells (CAR) phenotype that has been suggested to maintain the HSC pool.2 Leukemic stem cells (LSCs) may also benefit from the microenvironment, to favor their proliferation and resistance towards treatment, as demonstrated within the endosteal region. Given the structuring capacities of MSCs, they may represent a crucial target for LSCs to create their own microenvironment and prosper. Thus, major publications confirm that targeting the stromal support can help to eradicate LSCs in vivo.3

Others and we have shown that β-catenin, the terminal effector of canonical Wnt signaling, was overactivated in acute myeloid leukemia (AML) and correlated with a greater risk of relapses.4 Importantly, no mutations of β-catenin have been described in AML, suggesting that signaling defects are not only intrinsic to LSCs, but also result from abnormal niche behavior and activity. Interestingly, we have disclosed a new AML subtype where leukemic progenitors overexpress the focal adhesion kinase (FAK) protein, a key-signaling partner of integrins that is not expressed by immature normal progenitors.5 FAK was overexpressed in half of AML cases and correlated with poor prognosis. The overexpression of FAK conferred increased drug resistance to AML cells and its regulation was independent from adhesion, as described in other cancers. Furthermore, FAK and β-catenin activities were correlated in leukemic cells6 (Despeaux et al., in preparation). As our previous data had shown that FAK-expressing AML (FAK+ AML) and FAK− AML were two distinct entities that behaved oppositely in terms of Wnt signaling, we aimed to determine whether BM MSCs isolated from those AML patients exhibited specific structural or functional abnormalities relative to oxidative inflammatory and Wnt signaling.

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Acknowledgements

The authors acknowledge orthopedic surgery team, P Tessarotto, M Pezzutto and M Socco-Lucca for technical assistance, F L′Faqihi-Olive and V Duplan-Eche from the ‘Plateforme de cytométrie et tri cellulaire’ of IFR150 and ‘plateforme de gene profiling’ of Cancéropole-Toulouse. This study was supported by Association pour la Recherche sur le Cancer (No 8407), Institut National du Cancer (No 07/3D1616/IABC-23-8/NC-NG), Conseil Régional Midi-Pyrénées.

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Author notes

  1. P Bourin and C Racaud-Sultan: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm, U1043, Toulouse, France

    M Despeaux, J Bertrand & C Racaud-Sultan

  2. CNRS, U5282, Toulouse, France

    M Despeaux, J Bertrand & C Racaud-Sultan

  3. Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France

    M Despeaux, J Bertrand & C Racaud-Sultan

  4. EFS-PM, Laboratoire de thérapie cellulaire, Toulouse, France

    E Labat, M Gadelorge & P Bourin

  5. STROMALab UMR UPS/CNRS/EFS 5273, Toulouse, France

    E Labat, M Gadelorge & P Bourin

  6. Inserm U1031, Toulouse, France

    E Labat, M Gadelorge & P Bourin

  7. Centre de Recherche en Cancérologie de Toulouse, UMR 1037 Inserm, Université de Toulouse, ERL 5294 CNRS, Toulouse, France

    N Prade, C Demur & C Recher

  8. CHU Purpan, Service Clinique et Laboratoire d'Hématologie, Toulouse, France

    C Demur, C Recher & B Payrastre

  9. CHU Purpan, Service Clinique de Chirurgie Orthopédique et Traumatologique, Toulouse, France

    P Bonnevialle

  10. Institut des Maladies Métaboliques et Cardiovasculaires, Inserm U1048, Toulouse, France

    B Payrastre

Authors
  1. M Despeaux
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  2. E Labat
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  11. C Racaud-Sultan
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Corresponding author

Correspondence to C Racaud-Sultan.

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Despeaux, M., Labat, E., Gadelorge, M. et al. Critical features of FAK-expressing AML bone marrow microenvironment through leukemia stem cell hijacking of mesenchymal stromal cells. Leukemia 25, 1789–1793 (2011). https://doi.org/10.1038/leu.2011.145

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