Drosophilamodel 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 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.

GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway

“…Various studies demonstrated Erk MAPK pathway was involved in cellular proliferation and migration ( Khodosevich, 2009 ; Wu et al, 2014 ). Although p38 MAPK pathway is normally associated with anti-proliferative and apoptotic functions ( Wagner & Nebreda, 2009 ), it was also reported that p38 was implicated in pro-survival functions, including positively regulating proliferation, differentiation and anti-apoptosis ( Halawani et al, 2004 ; Ricote et al, 2006 ; Terriente-Félix et al, 2017 ; Thornton et al, 2008 ). MAPK/Erk, Akt and p38 MAPK pathways were required for the migration of cortical neurons upon HGF stimulation ( Segarra et al, 2006 ), however, we observed GDF11 significantly suppressed the migratory capacity of C17.2 neural stem cells with the activation of Erk MAPK, PI3K/Akt and p38 MAPK pathways.…”

GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway

“…Various studies demonstrated MAPK/Erk pathway was involved in cellular proliferation and migration (Khodosevich 2009;Wu et al 2014). Although p38 MAPK pathway is normally associated with anti-proliferative and apoptotic functions (Wagner & Nebreda 2009), it is also reported that p38 is implicated in prosurvival functions, including positively regulate proliferation, differentiation and antiapoptosis (Halawani et al 2004;Ricote et al 2006;Terriente-Félix et al 2017;Thornton et al 2008). MAPK/Erk, Akt and p38 MAPK pathways were required for the migration of cortical neurons upon HGF stimulation (Segarra et al 2006), however, we observed GDF11 significantly suppressed the capacity of C17.2 neural stem cells to migrate with the activation of Erk MAPK, PI3K/Akt andp38 MAPK pathways.…”

Regulation of Drosophila Hematopoiesis in Lymph Gland: From a Developmental Signaling Point of View

“…Larvae with a hop gain-of-function mutation always show hypertrophic lymph glands [ 68 ]. Consistently, ectopic expression of hop in the CZ, but not in the MZ, led to hyperplasia of the lymph gland, which requires Stat92E, Dome, and Upd3 [ 69 ]. In lymph glands with either the hop hypermorphic mutation or hop overexpression, an increased number of lamellocytes was also observed, even without parasitization [ 68 , 69 ].…”

“…Consistently, ectopic expression of hop in the CZ, but not in the MZ, led to hyperplasia of the lymph gland, which requires Stat92E, Dome, and Upd3 [ 69 ]. In lymph glands with either the hop hypermorphic mutation or hop overexpression, an increased number of lamellocytes was also observed, even without parasitization [ 68 , 69 ]. Together, these results suggest that JAK-STAT signaling possesses the ability to enhance blood cell proliferation and induce lamellocyte formation in lymph glands.…”