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Haematologica. 2019 Oct;104(10):2017-2027. doi: 10.3324/haematol.2018.205385. Epub 2019 Mar 28.

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL.

Author information

1
Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, F-33000 Bordeaux.
2
CHU Bordeaux, Service d'Hématologie Clinique et Thérapie cellulaire, F-33000, Bordeaux.
3
Université 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.
4
Service de Biologie des Tumeurs and Laboratoire d'Hématologie Biologique, Centre Hospitalo-Universitaire CHU Bordeaux, F-33000, Bordeaux.
5
Service Commun des Animaleries, Animalerie A2, Université de Bordeaux, Bordeaux.
6
Institut National de la Santé et de la Recherche Médicale INSERM U1218, and UMS005 TBM Core, Plateforme d'Histopathologie Expérimentale, Université de Bordeaux, F33000 Bordeaux.
7
Institut National de la Santé et de la Recherche Médicale, INSERM U1053, F33000 Bordeaux.
8
Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Paris, France.
9
Université 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 isabelle.dusanter@inserm.fr.
10
Université de Bordeaux, Institut National de la Santé et de la Recherche Médicale INSERM U1035, F-33000 Bordeaux jean-max.pasquet@u-bordeaux.fr.

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 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.

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