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Microenvironnement médullaire et résistance des LAM FLT3-ITD aux inhibiteurs de tyrosine kinase : Rôle pivot du récepteur TAM AXL

Abstract : Internal tandem duplication in Fms-like tyrosine kinase 3 gene (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML), and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors (FLT3-TKI) have been promising for therapeutic strategies but clinical trials have revealed rarely long-lasting remission with persistent leukemic cells present in the bone marrow. In this work, we show that the hematopoietic niche microenvironment protects FLT3-ITD AML cells from FLT3-TKI quizartinib (AC220) through convergent up-regulation of AXL expression and activity. Cytokine-dependent activation of STAT5 enhances AXL gene transcription and expression, while low O2 concentration up-regulates AXL protein levels. Moreover, cytokines such as thrombopoietin or interleukin-3 directly activate AXL. RNA interference-based inhibition of AXL expression in FLT3-ITD AML cells allowed a selective purge of leukemic cells within their microenvironment when combined with FLT3-TKI in immuno-compromised mice. Altogether, our data support a strategy combining FLT3-TKI and anti-AXL therapy to eradicate FLT3-ITD AML cells, including those protected by the hematopoietic niche. In such a setting, we performed a study to test the efficacy of gilteritinib (ASP2215) and we showed in vitro and in vivo that this dual FLT3/AXL-TKI is more efficient to eradicate leukemic cells in their microenvironment than quizartinib which is a more specific FLT3-TKI. Finally, we also studied an anti-AXL monoclonal antibody on primary AML cells and showed that its efficacy could be interesting with FLT3-TKI and cytarabine in both FLT3-wild type and FLT3-ITD AML.
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https://tel.archives-ouvertes.fr/tel-01823822
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Submitted on : Tuesday, June 26, 2018 - 2:57:15 PM
Last modification on : Tuesday, October 20, 2020 - 11:27:21 AM
Long-term archiving on: : Wednesday, September 26, 2018 - 9:54:09 PM

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  • HAL Id : tel-01823822, version 1

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Pierre-Yves Dumas. Microenvironnement médullaire et résistance des LAM FLT3-ITD aux inhibiteurs de tyrosine kinase : Rôle pivot du récepteur TAM AXL. Cancer. Université de Bordeaux, 2017. Français. ⟨NNT : 2017BORD0675⟩. ⟨tel-01823822⟩

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