AXL inhibition extinguishes primitive JAK2 mutated myeloproliferative neoplasm progenitor cells
AffiliationStem Cell and Leukaemia Proteomics Laboratory, Manchester Academic Health Science Centre, The University of Manchester, UK
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AbstractMyeloproliferative neoplasms (MPN) are clonal stem cell associated disorders inclusive of chronic myeloid leukemia (CML), Polycythaemia vera (PV), myelofibrosis (MF), and essential thrombocythemia (ET). They are characterized by increased production of myeloid cells with minimal effects on terminal differentiation but can undergo transformation to acute leukemias. PV is the most common chronic myeloproliferative neoplasm and in the majority of cases is characterized by a V617F point mutation in JAK2. This JAK2 activating mutation is also found in about half the patients with MF and ET. Such aberrant proteins offer great potential for the treatment of these diseases however inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. We have previously used advanced proteomic techniques to identify drug targets and thus develop novel treatment strategies to distinguish the leukemic clone in both CML and PV. Here, we build on our proteomic data sets to characterize a new target, the receptor tyrosine kinase AXL. AXL is overexpressed in acute myeloid leukemia and importantly small molecule inhibitors have been developed which are currently in clinical trial hence offer the opportunity to repurpose this drug for the treatment of MPNs. We demonstrate that AXL is upregulated and activated in JAK2 associated MPNs. Further we show that inhibition of AXL preferentially kills early hemopoietic stem cells from PV patients and as such represents a promising therapeutic approach for JAK2 driven MPNs
CitationPearson S, Blance R, Somervaille TCP, Whetton AD, Pierce A. AXL Inhibition Extinguishes Primitive JAK2 Mutated Myeloproliferative Neoplasm Progenitor Cells. Hemasphere. 2019;3(3):e233.
- Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond.
- Authors: Michiels JJ, Berneman Z, Schroyens W, De Raeve H
- Issue date: 2015
- The role of JAK2 V617F mutation, spontaneous erythropoiesis and megakaryocytopoiesis, hypersensitive platelets, activated leukocytes, and endothelial cells in the etiology of thrombotic manifestations in polycythemia vera and essential thrombocythemia.
- Authors: Bellucci S, Michiels JJ
- Issue date: 2006 Jun
- AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms.
- Authors: Beitzen-Heineke A, Berenbrok N, Waizenegger J, Paesler S, Gensch V, Udonta F, Vargas Delgado ME, Engelmann J, Hoffmann F, Schafhausen P, von Amsberg G, Riecken K, Beumer N, Imbusch CD, Lorens J, Fischer T, Pantel K, Bokemeyer C, Ben-Batalla I, Loges S
- Issue date: 2021 Sep
- 2016 WHO Clinical Molecular and Pathological Criteria for Classification and Staging of Myeloproliferative Neoplasms (MPN) Caused by MPN Driver Mutations in the JAK2, MPL and CALR Genes in the Context of New 2016 WHO Classification: Prognostic and Therapeutic Implications.
- Authors: Michiels JJ, Tevet M, Trifa A, Niculescu-Mizil E, Lupu A, Vladareanu AM, Bumbea H, Ilea A, Dobrea C, Georgescu D, Patrinoiu O, Popescu M, Murat M, Dragan C, Mihai F, Zurac S, Angelescu S, Iova A, Popa A, Gogulescu R, Popov V
- Issue date: 2016 Mar
- JAK2-v617F mutation is associated with clinical and laboratory features of myeloproliferative neoplasms.
- Authors: Duletić AN, Dekanić A, Hadzisejdić I, Kusen I, Matusan-Ilijas K, Grohovac D, Grahovac B, Jonjić N
- Issue date: 2012 Sep