Abstract
ABSTRACTMyeloproliferative 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 use Drosophila to 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 a Drosophila model of MPNs. Based on the shared molecular mechanisms underlying MPNs in flies and humans, the interplay between Drosophila JAK and p38 signalling pathways unravelled in this work might have translational relevance for human MPNs.
Highlights
Myeloproliferative neoplasms (MPNs) arise in patients having a gain-of-function mutation in Janus kinase 2 (JAK2) or the myeloproliferative leukaemia protein receptor (MPL)
We show that the p38 MAPK pathway contributes to this feed-forward loop by regulating expression of the ligand Upd3, and, most interestingly, when activated in maturing haemocytes, suffices to induce lymph gland hypertrophy and melanotic tumours
Here, we have analysed the impact of JAK overexpression in the different cell populations of the lymph gland, the major haematopoietic organ of Drosophila
Summary
Myeloproliferative neoplasms (MPNs) arise in patients having a gain-of-function mutation in Janus kinase 2 (JAK2) or the myeloproliferative leukaemia protein receptor (MPL). Received 3 October 2016; Accepted 1 February 2017 range These subtypes are less severe than some other types of MPNs, such as chronic myelogenous leukaemia, which is caused by the translocation BCR-Abl (Philadelphia chromosome), 15% of patients exhibit PMF and a small percentage develop acute myeloid leukaemia, both of which compromise life expectancy. In 2005, JAK2V617F was identified as one of the most common mutations causing the disease (Baxter et al, 2005; James et al, 2005; Kralovics et al, 2005; Pecquet et al, 2010) This mutation was shown in murine models to be sufficient to induce activation of the JAK2 pathway in the bone marrow, and to increase the rates of proliferation of myeloid cells (Lacout et al, 2006). Long before the causal role of JAK2V617F in MPNs was known, Drosophila JAK gain-of-function mutations were shown to cause hypertrophy of the fly haematopoietic organs (lymph glands), and enhanced proliferation of circulating blood cells (haemocytes) and melanotic tumours (Corwin and Hanratty, 1976; Luo et al, 1997; Minakhina and Steward, 2006; Myllymäki and Rämet, 2014; Sorrentino et al, 2002)
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