title: ADrosophilamodel of myeloproliferative neoplasm reveals a feed-forward loop in the JAK pathway mediated by p38 MAPK signalling.
abstract: Myeloproliferative neoplasms (MPNs) of the Philadelphia-negative class comprise polycythaemia vera, essential thrombocythaemia and primary myelofibrosis (PMF). They are associated with aberrant numbers of myeloid lineage cells in the blood, and in the case of overt PMF, with development of myelofibrosis in the bone marrow and failure to produce normal blood cells. These diseases are usually caused by gain-of-function mutations in the kinase JAK2. Here, we useDrosophilato investigate the consequences of activation of the JAK2 orthologue in haematopoiesis. We have identified maturing haemocytes in the lymph gland, the major haematopoietic organ in the fly, as the cell population susceptible to induce hypertrophy upon targeted overexpression of JAK. We show that JAK activates a feed-forward loop, including the cytokine-like ligand Upd3 and its receptor, Domeless, which are required to induce lymph gland hypertrophy. Moreover, we present evidence that p38 MAPK signalling plays a key role in this process by inducing expression of the ligand Upd3. Interestingly, we also show that forced activation of the p38 MAPK pathway in maturing haemocytes suffices to generate hypertrophic organs and the appearance of melanotic tumours. Our results illustrate a novel pro-tumourigenic crosstalk between the p38 MAPK pathway and JAK signalling in aDrosophilamodel of MPNs. Based on the shared molecular mechanisms underlying MPNs in flies and humans, the interplay betweenDrosophilaJAK and p38 signalling pathways unravelled in this work might have translational relevance for human MPNs.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Ana
authors.identifier: 0000-0003-4948-6219
authors.initials: A
authors.lastname: Terriente-Félix
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Pérez
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bray
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain angel.nebreda@irbbarcelona.org marco.milan@irbbarcelona.org.|ICREA, Pg. Lluís Companys 23, Barcelona 08010, Spain.
authors.forename: Angel R
authors.identifier: 0000-0002-7631-4060
authors.initials: AR
authors.lastname: Nebreda
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain angel.nebreda@irbbarcelona.org marco.milan@irbbarcelona.org.|ICREA, Pg. Lluís Companys 23, Barcelona 08010, Spain.
authors.forename: Marco
authors.identifier: 0000-0002-7111-6444
authors.initials: M
authors.lastname: Milán
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology*; D006434:Hemocytes / Q000378:metabolism; D006984:Hypertrophy; D053612:Janus Kinases / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009196:Myeloproliferative Disorders / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D014157:Transcription Factors; D053612:Janus Kinases; C085845:hop protein, Drosophila; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Drosophila; Haemocyte; Hypertrophy; JAK; Myeloproliferative neoplasm; p38 MAPK