@article{Pierre-Yves Dumas_Cécile Naudin_Séverine Martin-Lannerée_Brigitte Izac_Luana Casetti_Olivier Mansier_Benoît Rousseau_Alexandre Artus_Mélody Dufossée_Alban Giese_Pierre Dubus_Arnaud Pigneux_Vincent Praloran_Audrey Bidet_Arnaud Villacreces_Amélie Guitart_Noël Milpied_Olivier Kosmider_Isabelle Vigon_Vanessa Desplat_Isabelle Dusanter-Fourt_Jean-Max Pasquet_2019, place={Pavia, Italy}, title={Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL}, volume={104}, url={https://haematologica.org/article/view/9085}, DOI={10.3324/haematol.2018.205385}, abstractNote={Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation 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-ITD clones.}, number={10}, journal={Haematologica}, author={Pierre-Yves Dumas and Cécile Naudin and Séverine Martin-Lannerée and Brigitte Izac and Luana Casetti and Olivier Mansier and Benoît Rousseau and Alexandre Artus and Mélody Dufossée and Alban Giese and Pierre Dubus and Arnaud Pigneux and Vincent Praloran and Audrey Bidet and Arnaud Villacreces and Amélie Guitart and Noël Milpied and Olivier Kosmider and Isabelle Vigon and Vanessa Desplat and Isabelle Dusanter-Fourt and Jean-Max Pasquet}, year={2019}, month={Sep.}, pages={2017-2027} }