Open AccessAXL Inhibition Represents a Novel Therapeutic Approach in BCR‐ABL Negative Myeloproliferative Neoplasms
Author(s) -
BeitzenHeineke Antonia,
Berenbrok Nikolaus,
Waizenegger Jonas,
Paesler Sarina,
Gensch Victoria,
Udonta Florian,
Vargas Delgado Maria Elena,
Engelmann Janik,
Hoffmann Friederike,
Schafhausen Philippe,
Amsberg Gunhild,
Riecken Kristoffer,
Beumer Niklas,
Imbusch Charles D.,
Lorens James,
Fischer Thomas,
Pantel Klaus,
Bokemeyer Carsten,
BenBatalla Isabel,
Loges Sonja
Publication year - 2021
Publication title -
hemasphere
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/hs9.0000000000000630
Subject(s) - myelofibrosis , ruxolitinib , polycythemia vera , cancer research , myeloid leukemia , myeloproliferative neoplasm , janus kinase 2 , myeloid , axl receptor tyrosine kinase , medicine , pharmacology , tyrosine kinase , jak stat signaling pathway , receptor , bone marrow
BCR‐ABL negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the JAK2 ‐activating mutation V617F. JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest‐specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and AKT signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.