Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.</p

Recent sedimentology at the grounding zone of the Kamb Ice stream, West Antarctica and implications for ice shelf extent

Sediment accumulating beneath floating ice contains a record of ice dynamics in polar regions where in situ observations are rare. In 2019 a hole was melted through a 590m-thick region of the Ross Ice Shelf ∼5 km seawards of the Kamb Ice Stream (KIS) grounding line (82.7841°S, 155.2626°W) to access the seafloor. Imagery from a remotely operated vehicle (ROV, Icefin) shows ocean current-generated ripples likely formed by tidal flow parallel to the grounding line (GL). Observed current speeds 30 ka or 14C dead. By contrast, 210Pb-210 activity of >30 Bq Kg−1 indicates deposition within the last 120 years. The combination of features suggests rapid rainout deposition from melting of a sediment-laden basal debris layer as the GL retreated, followed by some reworking by ocean currents and little modern accumulation. Although Tertiary diatoms are abundant, unambiguously Late Quaternary forms are absent and we speculate on the implications for Ross Ice Shelf stabilit

Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

Summary: The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis