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Acute Myeloid Leukemia
Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5- and hypoxia-dependent upregulation of AXL
Ferrata Storti Foundation
Haematologica 2019 Volume 104(10):2017-2027
Pierre-Yves Dumas,1,2* Cécile Naudin,3* Séverine Martin-Lannerée,3 Brigitte Izac,3 Luana Casetti,3 Olivier Mansier,4 Benoît Rousseau,5 Alexandre Artus,3 Mélody Dufossée,1 Alban Giese,6 Pierre Dubus,6,7 Arnaud Pigneux,1,2 Vincent Praloran,1,2 Audrey Bidet,4 Arnaud Villacreces,1 Amélie Guitart,1 Noël Milpied,1,2 Olivier Kosmider,3,8 Isabelle Vigon,1 Vanessa Desplat,1 Isabelle Dusanter-Fourt,3** and Jean-Max Pasquet1**
1Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, F-33000 Bordeaux; 2CHU Bordeaux, Service d’Hématologie Clinique
et Thérapie cellulaire, F-33000, Bordeaux; 3Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris; 4Service de Biologie des Tumeurs and Laboratoire d’Hématologie Biologique, Centre Hospitalo-Universitaire CHU Bordeaux, F-33000, Bordeaux; 5Service Commun des Animaleries, Animalerie A2, Université de Bordeaux, Bordeaux; 6Institut National de la Santé et de la Recherche Médicale INSERM U1218, and UMS005 TBM Core, Plateforme d’Histopathologie Expérimentale, Université de Bordeaux, F33000 Bordeaux; 7Institut National de la Santé et de la Recherche Médicale, INSERM U1053, F33000 Bordeaux and 8Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Paris, France
*P-YD and CN contributed equally to this work. **ID-F and J-MP contributed equally as co-senior authors.
ABSTRACT
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 damp- ening 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 microenviron- ment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sus- tained phosphorylation of the transcription factor STAT5 in quizartinib- treated cells, which enhanced AXL expression by direct binding of a con- served 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 quizar- tinib through combined upregulation of AXL activity. Targeting this signal- ing offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby pre- venting relapses from FLT3-ITD clones.
Introduction
The Fms-like tyrosine kinase 3 (FLT3) gene encodes a class III receptor tyrosine- kinase (RTK) that is well expressed in hematopoietic stem progenitor cells (HSPC) and strongly activates PI3K/AKT and MAPK pathways upon ligand binding.1 Internal tandem duplication (ITD) in FLT3 is one of the most frequent mutations
Correspondence:
JEAN-MAX PASQUET
jean-max.pasquet@u-bordeaux.fr
ISABELLE DUSANTER-FOURT
isabelle.dusanter@inserm.fr
Received:
September 12, 2018. Accepted: March 21, 2019. Pre-published: March 28, 2019.
doi:10.3324/haematol.2018.205385
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/10/2017
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haematologica | 2019; 104(10)
2017
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