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P.-Y. Dumas et al.
of its destabilizers, the prolyl 4-hydroxylase domain pro- tein 3 (PHD3) in both normal hematopoietic progenitors and leukemic cells.27 Such activities might reinforce the hypoxia-induced message coming directly from the microenvironment and strengthen AXL overexpression.
Finally, our data show that the hematopoietic niche pro- vides selective signals regulating AXL expression. This plays a pivotal role in the selective response of FLT3-ITD AML cells to quizartinib within the specific location of the bone marrow, where leukemic stem cells are well main- tained. Our study suggests that, in addition to the dual inhibition of AXL and FLT3 through TKI combination or a dual TK inhibitor such as gilteritinib, targeting AXL upstream signaling steps could be investigated in targeting FLT3-ITD AML-initiating cells in the hematopoietic niche.9,50
Acknowledgments
We thank Mrs. Bernadette De Buhan and her family for their generous support. We thank the Cytometry and Genomic Facilities of Institut Cochin/Inserm U1016, the Cytometry Facility, Vectorology Facility, Animals Facility and Histology Facility of FR TransBioMed, Bordeaux University, for performing cell sorting, microarray screening and handling animals. We thank the Obstetric Unit at Orsay Hospital and the Cell Therapy Center at St-Louis hospital (Paris, France) for providing CB samples. P-YD was a recipient of the SIRIC Brio for research fellowship for one year, then the MD-PhD program from the University Hospital of Bordeaux for two years. CN and SM-L
were fellows of the “Association pour la recherche contre le Cancer”, “Ligue Nationale contre le Cancer” and Région Ile de France DIM-Biothérapies.We thank David Galeazzi for accu- rate data collection concerning patients at Bordeaux University Hospital. We also acknowledge the Centre de Ressources Biologiques Cancer, Bordeaux Biothèques Santé (BB-0033- 00036) at Bordeaux University Hospital as well as the CRBP at the Hematology unit at Cochin Hospital (CPP: 2015-08-11 DC) for providing biological material.
Funding
AG was funded by the SIRIC Brio (grant INCa-DGOS- Inserm 6046) for his work at the UMS 005 TBM Core histopathology platform. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Paris-Descartes University, Agence Nationale de Recherche (ANR-2011-RPIB-009-04), Ligue Nationale contre le Cancer (RS13/75-6; EL2014-3), Ligue Régionale contre le Cancer (Comité Pyrénées Atlantique et comité Ile de Paris) and Cancéropôle Grand Sud-Ouest (2015-0389). We thank the data management unit at Toulouse University Hospital and the CAPTOR (Cancer Pharmacology of Toulouse Oncopole and Region) project (ANR-11-PHUC-001) for its financial support enabling e-CRF for the AML database. The funders had no role in study design, data collection or analysis, decision to publish or preparation of the manuscript. We thank Prof. D. Bouscary, Dr P. Auberger and Dr E. Lauret for their crit- ical reading of the manuscript.
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