Authors
Kangboonruang, K., Drabent, P., Heintze, M., Maksut, F., Lepelletier, Y., Lhermitte, L., Feroul, M., Letard, S., Kabore, C., Brenet, F., Meni, C., Cagnard, N., Bondet, V., Lefevre, G., Bruneau, J., Dussiot, M., Halse, H., Bigorgne, A., Collange, A.-F., Bouktit, H., Retornaz, F., Megret, J., Barete, S., Droin, N., Bulai Livideanu, C., Lebouvier, A., Duffy, D., Solary, E., Arock, M., Gandhi, D., Bodemer, C., Rossignol, J., Polivka, L., Molina, T., Hermine, O., Maouche-Chretien, L.
Abstract
Mastocytosis is a clonal disorder driven by KIT mutations, yet resistance to tyrosine kinase inhibitors (TKIs) remains a major challenge. Following the discovery of an AXL L197M mutation in a patient with congenital aggressive mastocytosis, we demonstrated unexpected expression of wild-type AXL in neoplastic mast cells (MCs) across mastocytosis subtypes, challenging current knowledge of mastocytosis pathophysiology. Interestingly, AXL was undetectable in steady-state MCs, whereas various factors including IFN- and IFN-{beta} induced its expression, consistent with the inflammatory nature of mastocytosis and elevated interferon levels detected in patient plasma. Ectopic expression of WT or L197M AXL in the ROSA KIT D816V cell line enhanced proliferation and survival by upregulating pSTAT5, pSTAT3, pFAK, p-p38, survivin and BCL2. Both AXL forms conferred resistance to the KIT inhibitor PKC412/midostaurin by sustaining BCL2, MCL1, and BCL-XL expression while reducing caspase-3 activation. Although L197M AXL induced slightly higher resistance to apoptosis than WT, no major differences observed. Combined KIT and AXL targeting (PKC412+R428) restored TKI sensitivity by downregulating BCL-XL, Livin, cIAP1, and activating caspase-3, highlighting the therapeutic potential of dual KIT/AXL pathway inhibition. Importantly, neoplastic MCs from a mast cell leukemia patient unresponsive to PKC412 and carrying the KIT F522C mutation strongly expressed AXL and displayed marked in vitro sensitivity to R428 alone, highlighting AXL as a potential therapeutic target in agressive mastocytosis not driven by KIT D816V. Collectively, these findings identify AXL as a previously unrecognized driver of malignant MC survival and TKI resistance, and support AXL inhibition as a promising therapeutic strategy in aggressive mastocytosis.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Nov 2025.
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