AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms
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, treatmen...
Main Authors: | , , , , , , , , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
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Wiley
2021-09-01
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Series: | HemaSphere |
Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000630 |
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author | Antonia Beitzen-Heineke Nikolaus Berenbrok Jonas Waizenegger Sarina Paesler Victoria Gensch Florian Udonta Maria Elena Vargas Delgado Janik Engelmann Friederike Hoffmann Philippe Schafhausen Gunhild von Amsberg Kristoffer Riecken Niklas Beumer Charles D. Imbusch James Lorens Thomas Fischer Klaus Pantel Carsten Bokemeyer Isabel Ben-Batalla Sonja Loges |
author_facet | Antonia Beitzen-Heineke Nikolaus Berenbrok Jonas Waizenegger Sarina Paesler Victoria Gensch Florian Udonta Maria Elena Vargas Delgado Janik Engelmann Friederike Hoffmann Philippe Schafhausen Gunhild von Amsberg Kristoffer Riecken Niklas Beumer Charles D. Imbusch James Lorens Thomas Fischer Klaus Pantel Carsten Bokemeyer Isabel Ben-Batalla Sonja Loges |
author_sort | Antonia Beitzen-Heineke |
collection | DOAJ |
description | 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. |
first_indexed | 2024-03-07T16:41:30Z |
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institution | Directory Open Access Journal |
issn | 2572-9241 |
language | English |
last_indexed | 2024-03-07T16:41:30Z |
publishDate | 2021-09-01 |
publisher | Wiley |
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series | HemaSphere |
spelling | doaj.art-9926bcade61949f78f7e494d63999f602024-03-03T08:11:36ZengWileyHemaSphere2572-92412021-09-0159e63010.1097/HS9.0000000000000630202109000-00002AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative NeoplasmsAntonia Beitzen-Heineke0Nikolaus Berenbrok1Jonas Waizenegger2Sarina Paesler3Victoria Gensch4Florian Udonta5Maria Elena Vargas Delgado6Janik Engelmann7Friederike Hoffmann8Philippe Schafhausen9Gunhild von Amsberg10Kristoffer Riecken11Niklas Beumer12Charles D. Imbusch13James Lorens14Thomas Fischer15Klaus Pantel16Carsten Bokemeyer17Isabel Ben-Batalla18Sonja Loges191 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany3 Division of Personalized Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany5 Practice for Hematology and Oncology Altona, Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany6 Department of Stem Cell Transplantation, Research Department Cell and Gene Therapy, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany3 Division of Personalized Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany7 Division of Applied Bioinformatics, German Cancer Research Center (Deutsches Krebsforschungszentrum; DKFZ), Heidelberg, Germany9 Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Norway11 Department of Hematology and Oncology, Medical Center, Otto-von-Guericke University, Magdeburg, Germany2 Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, Germany1 Department for Oncology, Hematology and Bone Marrow Transplantation with the Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, GermanyBCR-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.http://journals.lww.com/10.1097/HS9.0000000000000630 |
spellingShingle | Antonia Beitzen-Heineke Nikolaus Berenbrok Jonas Waizenegger Sarina Paesler Victoria Gensch Florian Udonta Maria Elena Vargas Delgado Janik Engelmann Friederike Hoffmann Philippe Schafhausen Gunhild von Amsberg Kristoffer Riecken Niklas Beumer Charles D. Imbusch James Lorens Thomas Fischer Klaus Pantel Carsten Bokemeyer Isabel Ben-Batalla Sonja Loges AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms HemaSphere |
title | AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms |
title_full | AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms |
title_fullStr | AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms |
title_full_unstemmed | AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms |
title_short | AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms |
title_sort | axl inhibition represents a novel therapeutic approach in bcr abl negative myeloproliferative neoplasms |
url | http://journals.lww.com/10.1097/HS9.0000000000000630 |
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