A Novel Subtype of Myeloproliferative Neoplasms Driven by a MYC-Alarmin Axis

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients whose MPNs lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves various hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. SIGNIFICANCE This study establishes that MYC expression is increased in triple negative MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in triple negative MPN. ### Competing Interest Statement D.J.M. has received funding from Merck Pharmaceuticals and PUMA Biotech for work unrelated to this project. A.T.K. received research funding from Bristol Myers Squibb, Novartis, Morphosys, GlaxoSmithKline, Janssesn. A.T.K. received honoraria from Abbvie, GlaxoSmithKline, MorphoSys, Incyte, Bristol Myers Squibb, CTI Biopharma, Kartos, and Karyopharm.