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.

IFN-Induced PARPs-Sensors of Foreign Nucleic Acids?

Cells have developed different strategies to cope with viral infections. Key to initiating a defense response against viruses is the ability to distinguish foreign molecules from their own. One central mechanism is the perception of foreign nucleic acids by host proteins which, in turn, initiate an efficient immune response. Nucleic acid sensing pattern recognition receptors have evolved, each targeting specific features to discriminate viral from host RNA. These are complemented by several RNA-binding proteins that assist in sensing of foreign RNAs. There is increasing evidence that the interferon-inducible ADP-ribosyltransferases (ARTs; PARP9-PARP15) contribute to immune defense and attenuation of viruses. However, their activation, subsequent targets, and precise mechanisms of interference with viruses and their propagation are still largely unknown. Best known for its antiviral activities and its role as RNA sensor is PARP13. In addition, PARP9 has been recently described as sensor for viral RNA. Here we will discuss recent findings suggesting that some PARPs function in antiviral innate immunity. We expand on these findings and integrate this information into a concept that outlines how the different PARPs might function as sensors of foreign RNA. We speculate about possible consequences of RNA binding with regard to the catalytic activities of PARPs, substrate specificity and signaling, which together result in antiviral activities.