ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis mediated neoplastic fibrocyte generation in myeloproliferative neoplasms.

Abstract

Apart from the central role of activated JAK/STAT signaling pathway, ASXL1 mutations are the most recurrent additional mutations in myeloproliferative neoplasms (MPNs) and occurred much more common in myelofibrosis (MF) than essential thrombocythemia (ET) and polycythemia vera (PV) patients. However, the mechanism of the association with ASXL1 mutations and bone marrow (BM) fibrosis remains unknown. Here, integrating our own data of MPN patients and hematopoietic-specific Asxl1 deletion/Jak2V617F mouse model, we show that ASXL1 mutations are associated with advanced MPN phenotypes and onset of myelofibrosis. ASXL1 mutations induce skewed monocyte/macrophage and neoplastic monocyte-derived fibrocyte differentiation, consequently enhance inflammation and BM fibrosis. Consistently, the loss of ASXL1 and JAK2V617F mutation in hematopoietic stem and progenitor cells (HSPCs) leads to enhancer activation of polycomb group (PcG) target genes, such as EGR1. The upregulation of EGR1, in turn accounts for increased HSPCs commitment to monocyte/macrophage lineage. Moreover, EGR1 induces the activation of TNFA and thereby further drives the differentiation of monocytes to fibrocytes. Accordingly, combined TNFR antagonist with ruxolitinib significantly reduces fibrocytes production in vitro. Altogether, these findings demonstrate that ASXL1 mutations accelerate fibrocyte production and inflammation in MPNs via EGR1-TNFA axis, providing cellular and molecular basis for BM fibrosis and proof-of-concept for anti-fibrosis treatment.