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Acute Leukemias

Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL

Leukemia volume 27, pages 305–314 (2013)Cite this article

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Abstract

Constitutively activated FLT3 signaling is common in acute myeloid leukemia, and is currently under evaluation for targeted therapy, whereas little data is available in T-cell acute lymphoblastic leukemia (T-ALL). We analyzed 357 T-ALL cases for FLT3 mutations and transcript expression. FLT3 mutations (3% overall) and overexpression (FLT3 high expresser (FLT3High)) were restricted to immature/TCRγδ T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3High T-ALLs and did not correlate with mutational status. In order to investigate the mechanisms of primary resistance to FLT3 inhibition, a broad quantitative screen for receptor kinome transcript deregulation was performed by Taqman Low Density Array. FLT3 deregulation was associated with overexpression of a network of receptor kinases (RKs), potentially responsible for redundancies and sporadic response to specific FLT3 inhibition. In keeping with this resistance to FLT3 inhibition could be reversed by dual inhibition of FLT3 and KIT with a synergistic effect. We conclude that immature T-ALL may benefit from multitargeted RK inhibition and that exploration of the receptor kinome defines a rational strategy for testing multitarget kinase inhibition in malignant diseases.

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Acknowledgements

We thank all the biologists and clinicians of the LALA/GRAALL adult and FRALLE pediatric French ALL groups for providing T-ALL samples and results. This work was supported by grants from the Association Cent Pour Sang La Vie and the association Laurette Fugain. We thank the Necker-Enfants-Malades department of pediatric cardiac surgery for providing thymic material.

LL and RBA performed research, data analysis and wrote the paper. PV, ML, NB and ASB performed research. VG performed statistical data analysis. HD and OH performed data analysis. EM and VA oversaw conceptual development of the project and wrote the paper.

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Authors and Affiliations

  1. Department of Hematology, Hôpital Necker-Enfants-Malades APHP, CNRS UMR 8147, Université Paris-5 Descartes, Paris, France

    L Lhermitte, R Ben Abdelali, P Villarèse, N Bedjaoui, A Trinquand, M Libura, A S Bedin, O Hermine, E Macintyre & V Asnafi

  2. Laboratoire d’Exploration fonctionnelle des Génomes, CEA, Génopole, Evry, France

    V Guillemot

  3. Department of Hematology, Hôpital Armand Trousseau, Paris, France

    A Petit & G Leverger

  4. Department of Hematology, Hôpital St-Louis, Paris, France

    H Dombret

  5. PRES LUNAM, CHU Angers service des Maladies du Sang et INSERM U 892, Angers, France

    N Ifrah

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  1. L Lhermitte
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Correspondence to V Asnafi.

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LL and RBA performed research, data analysis and wrote the paper. PV, ML, NB and ASB performed research. VG performed statistical data analysis. HD and OH performed data analysis. EM and VA oversaw conceptual development of the project and wrote the paper.

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Lhermitte, L., Ben Abdelali, R., Villarèse, P. et al. Receptor kinase profiles identify a rationale for multitarget kinase inhibition in immature T-ALL. Leukemia 27, 305–314 (2013). https://doi.org/10.1038/leu.2012.177

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