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    Acute myeloid leukemia: identification of a microenvironment-dependent rescue mechanism against FLT3 targeted therapy

    Study co-directed by Isabelle Dusanter-Fourt

    Isabelle Dusanter-Fourt’s group in the team “normal and pathological hematology” headed by Michaela Fontenay/Didier Bouscary,

    in collaboration with Jean-Max Pasquet’s team (INSERM U1035/Bordeaux University), in a paper published in the journal Haematologica from October 2019, showed how acute myeloid leukemia cells with FLT3 receptor mutations escape from anti-FLT3 targeted therapy, thanks to their microenvironment that induces over-expression and over-activation of a new tyrosine receptor, AXL. This new receptor thus rescues FLT3 activity. These data offer the prospect of a new therapy to eradicate anti-FLT3 resistant leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-driven AML. 


    Mutations in the receptor Fms-like tyrosine kinase 3 (FLT3)like internal tandem duplications, are the most frequent mutations observed in acute myeloid leukemia and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors have been developed for targeted therapy. They were tested in clinical trials with variable benefits according to disease heterogeneity but also to the development of short-duration remission due to the rapid emergence of resistance. Hematopoietic stem progenitor cells as well as the derived leukemic cells are formed in the bone marrow, where they interact with their microenvironment, the so-called hematopoietic niche. Here, mechanisms dampening response to FLT3 inhibitor quizartinib, specific to the hematopoietic niche, were investigated. 


    Using AML primary samples and cell lines, Isabelle Dusanter-Fourt's team demonstrated that convergent signals from hematopoietic microenvironment drive FLT3 mutant cells resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines secreted by stromal cells sustain phosphorylation of the transcription factor STAT5 in quizartinib-treated cells which enhances AXL expression by direct binding of a conserved motif in AXL genomic sequence; they also enhanced AXL activity. Likewise, hypoxia, another well-agreed hematopoietic niche hallmark, also enhances AXL expression. A xenograft mouse model with leukemia cells knocked down for AXL, has been developed; these cells were introduced in animals either subcutaneously or through intravenous injection that leads to the restricted homing of the leukemic cells in the bone marrow niche. Loss of AXL significantly increases FLT3 mutated leukemic cells response to quizartinib when located in a bone marrow environment selectively; it has no impact when leukemic cells were injected subcutaneously. 


    These data highlight a new bypass mechanism, specific to the hematopoietic niche, that hampers the response to quizartinib through up-regulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3 mutated leukemic cells.


    Figure legend: Oncogenic activity of FLT3 receptors expressed in acute myeloid leukemia cells uses the transcription factor STAT5 to mediate cell growth and survival. Upon anti-FLT3 therapy, STAT5 gets no longer activated by FLT3. Hypoxia and cytokines secreted by the microenvironment activate STAT5, which binds to AXL genomic sequence and enhances its expression; they also activate the receptor, which supports leukemia cell maintenance. Leukemia cells become AXL addicted for their growth, which make then perfect targets for combined anti-FLT3 and anti-AXL therapeutic treatments. 



    Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL. Dumas PY, Naudin C, Martin-Lannerée S, Izac B, Casetti L, Mansier O, Rousseau B, Artus A, Dufossée M, Giese A, Dubus P, Pigneux A, Praloran V, Bidet A, Villacreces A, Guitart A, Milpied N, Kosmider O, Vigon I, Desplat V, Dusanter-Fourt I, Pasquet JM. Haematologica. 2019, 104(10):2017-2027.

    Associated editorial by Anna Orlova et al:

    The stromal microenvironment provides an escape route from FLT3 inhibitors through the GAS6-AXL-STAT5 axis. Orlova A, Neubauer HA, Moriggl R. Haematologica. 2019, 104(10):1907-1909.


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