Centre de Référence Maladies Rares

U1035 INSERM

Biotherapy of genetic diseases, inflammatory disorders and cancers (BMGIC)

FR: Biologie Fondamentale Appliquée à la Médecine

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Normal and Leukemic Hematopoietic Stem Cells team
Project 4.1

Oncogneic kinase signaling in acute myeloid leukemia

keywords: AML, leukemic stem cells (LSC)

Description:

Projects aim to study the oncogenic cooperation of Kinases in acute myeloid leukemia (AML), resistance to therapy and survival of leukemic stem cells (LSC) of AML, molecular and functional characterization of LSC maintenance mechanisms and the pre-leukemic hematopoiesis in particular studying the transcriptome, the kinome, immunologicalsurveillance and the metabolism of various immature hematopoietic compartments in the diagnosis and relapse.

  • Study of kinases oncogenic cooperation in acute myeloid leukemia (AML) :
    Our goals are to determine how some kinases and particularly tyrosine kinases (TK) are involved in the leukemogenesis of AML and whether in hematopoietic niche conditions they have control of the persistence of stem cells maintaining quiescence / dormancy, a specific location or a particular interaction with the bone marrow microenvironment. One of these relates TK Axl whose expression and phosphorylation increase in the conditions of the hematopoietic niche. We study its role in in vitro treatment resistance and maintenance of the stem cell in in vivo xenografts. We then have the opportunity to validate its therapeutic targeting different approaches including the use of new inhibitors but also by immunotherapy as part of collaboration with the Institute of Cancer Research in Montpellier.
  • Resistance to therapy and survival of leukemic stem cells (LSC) AML : Identification and characterization of kinases involved in chemoresistance :
    AML is characterized by significant heterogeneity both at the molecular level and phenotype. More than a third of AML have mutations on the receptor tyrosine kinase FLT3 (tandem duplication “ITD” or kinase domain mutation “TKD”). We study the expression and signaling of several kinases involved in resistance to chemotherapy and relapse of AML participating directly or indirectly to an oncogenic support. For this we have a limited number of patients analyzed their expression and activity. We will validate these results in a larger cohort (> 100 patients). We study the role of these kinases in vivo by xenograft to characterize their role in the maintenance of LSC and thus offer a therapeutic targeting and improved therapeutic management of AML.
  • Molecular and functional characterization of retention mechanisms LSC and pre-leukemic hematopoiesis :
    Leukemic relapse is related to the persistence of LSC capable of initiating disease or reinitiating after treatment but also to the existence of pre-leukemic clones acquiring new transformative anomalies. These cells may secondarily generate resistant clones to initial treatment. The objective is to study (in vitro and by xenograft) mechanisms that allow maintaining a pre-leukemic hematopoiesis and survival of LSCs within the hematopoietic niche (bone marrow). The in vitro modeling of different pre-leukemic anomalies enables the characterization of different mechanisms of maintenance while determining if intrinsic or extrinsic factors of the hematopoietic niche are involved.
  • Mechanism of immunosurveillance and metabolic adaptation maintaining LSC :
    In collaboration with several local research teams (French Blood Establishment Aquitaine Limousin, Resonance Center of Magnetic Biological Systems, ImmunoConcEpT, proteomics platform), we are studying the transcriptome, the kinome and the metabolome of the LSC of AML in the conditions of the hematopoietic niche. These approaches will also be used to understand the maintenance of pre-leukemic hematopoiesis focusing primarily on the mechanisms of immuno surveillance and metabolic adaptation inside the hematopoietic niche.

Related publications:

  • Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia-induced quiescence. Ianniciello A, Dumas PY, Drullion C, Guitart A, Villacreces A, Peytour Y, Chevaleyre J, Brunet de la Grange P, Vigon I, Desplat V, Priault M, Sbarba PD, Ivanovic Z, Mahon FX, Pasquet JM. Oncotarget. (2017-06) PMID: 29228587
  • Azacitidine or intensive chemotherapy for older patients with secondary or therapy-related acute myeloid leukemia. Dumas PY, Bertoli S, Bérard E, Médiavilla C, Yon E, Tavitian S, Leguay T, Huguet F, Forcade E, Milpied N, Sarry A, Sauvezie M, Bories P, Pigneux A, Récher C. Oncotarget. (2017-03) PMID: 29108292
  • Apoptosis and autophagy play opposite roles on Imatinib-induced K562 leukemia cells senescence. DRULLION C, TREGOAT C, LAGARDE V, TAN S, GIOIA R, PRIAULT M, DJAVAHERI-MERGNY M, BRISSON A, AUBERGER P, MAHON FX, PASQUET JM. Cell Death and Dis. (2015-08-16) 3:e373
  • CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukemia. GIOIA R, TREGOAT C, DUMAS PY, LAGARDE V, PROUZET-MAULEON V, DESPLAT V, SIRVENT A, PRALORAN V, LIPPERT E, VILLACRECES A, LECONET W, ROBERT B, VIGON I, ROCHE S, MAHON FX, PASQUET JM. Jour Pathol. (2015) DOI: 10.1002/path.4561
  • Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration. Thierry S, Benleulmi MS, Sinzelle L, Thierry E, Calmels C, Chaignepain S, Waffo-Teguo P, Merillon JM, Budke B, Pasquet JM, Litvak S, Ciuffi A, Sung P, Connell P, Hauber I, Hauber J, Andreola ML, Delelis O, Parissi V. Chem Biol (2015) 10.1016/j.chembiol.2015.04.020
  • Loss of SYK and LYN tyrosine kinase expression impair ponatinib-induced apoptosis in K562 cells. LAGARDE V, MAHON FX, PASQUET JM. Journal of Translational Proteomics Research (2015)
  • p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells. TROCOLI A, BENSADOUN P, RICHARD E, LABRUNIE G, MERHI F, SCHLÄFLI AM, BRIGGER D, SOUQUERE S, PIERRON G, PASQUET JM, SOUBEYRAN P, REIFFERS J, SÉGAL-BENDIRDJIAN E, TSCHAN MP, DJAVAHERI-MERGNY M. Cell Death Differ. (2014) doi: 10.1038/cdd.2014
  • Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy. LECONET W, LARBOURET C, CHARDÈS T, THOMAS G, NEIVEYANS M, BUSSON M, JARLIER M, RADOSEVIC-ROBIN N, PUGNIÈRE M, BERNEX F, PENAULT-LLORCA F, PASQUET JM, PÈLEGRIN A, ROBERT B. Oncogene. (2013-11-18)
  • Variable Behavior of iPSCs Derived from CML Patients for Response to TKI and Hematopoietic Differentiation. BEDEL A, PASQUET JM, LIPPERT E, TAILLEPIERRE M, LAGARDE V, DABERNAT S, DUBUS P, CHARAF L, BELIVEAU F, DE VERNEUIL H, RICHARD E, MAHON FX, MOREAU-GAUDRY F. PLoS One. (2013-08-23) 8(8):e71596
  • Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 inhibits its activity and promotes cell survival. TAOUJI S, HIGA A, DELOM F, PALCY S, MAHON FX, PASQUET JM, BOSSÉ R, SÉGUI B, CHEVET E. J Biol Chem. (2013-06-14) 288(24):17190-201
  • Mycophenolic acid overcomes imatinib and nilotinib resistance of chronic myeloid leukemia cells by apoptosis or a senescent-like cell cycle arrest. DRULLION C, LAGARDE V, GIOIA R, LEGEMBRE P, PRIAULT M, CARDINAUD B, LIPPERT E, MAHON FX, PASQUET JM. Leuk.Res.Treat. (2012) ID 861301, 9
  • Imatinib triggers mesenchymal-like conversion of CML cells associated with increased aggressiveness. PUISSANT A, DUFIES M, FENOUILLE N, BEN SAHRA I, JACQUEL A, ROBERT G, CLUZEAU T, DECKERT M, TICHET M, CHELI Y, CASSUTO JP, RAYNAUD S, LEGROS L, PASQUET JM, MAHON FX, LUCIANO F, AUBERGER P. J Mol Cell Biol. (2012) 4(4):207-20
  • Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells. GIOIA R, LEROY C, DRULLION C, LAGARDE V, ETIENNE G, DULUCQ S, LIPPERT E, ROCHE S, MAHON F, PASQUET JM. Blood. (2011) 118(8) : 2211-2221

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