Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis

Vincelette, ND; Yu, X; Kuykendall, AT; Moon, J; Su, S; Cheng, CH; Sammut, R; Razabdouski, TN; Nguyen, HV; Eksioglu, EA; Chan, O; Al Ali, N; Patel, PC; Lee, DH; Nakanishi, S; Ferreira, RB; Hyjek, E; Mo, Q; Cory, S; Lawrence, HR; Zhang, L; Murphy, DJ; Komrokji, RS; Lee, D; Kaufmann, SH; Cleveland, JL; Yun, S

Author(s): Vincelette, ND; Yu, X; Kuykendall, AT; Moon, J; Su, S; Cheng, CH; Sammut, R; Razabdouski, TN; Nguyen, HV; Eksioglu, EA; Chan, O; Al Ali, N; Patel, PC; Lee, DH; Nakanishi, S; Ferreira, RB; Hyjek, E; Mo, Q; Cory, S; Lawrence, HR; Zhang, L; Murphy, DJ; Komrokji, RS; Lee, D; Kaufmann, SH; Cleveland, JL; Yun, S;
Details: Publication Year 2024-05-07,Volume 5,Issue #4,Page 276-297
Journal Title: Blood Cancer DIscovery
Abstract: 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 who 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 numerous 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.
Publisher: AACR
Keywords: *Chromosomes, Human, Pair 8/genetics; Humans; *Trisomy/genetics; *Proto-Oncogene Proteins c-myc/genetics/metabolism; *Calgranulin B/genetics/metabolism; *Myeloproliferative Disorders/genetics/metabolism/pathology; Animals; Mice; Primary Myelofibrosis/genetics/pathology/metabolism; Signal Transduction/genetics
Research Division(s): Blood Cells And Blood Cancer
PubMed ID: 38713018
Publisher's Version: https://doi.org/10.1158/2643-3230.BCD-23-0210
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-05-20 07:53:44

Last Modified: 2024-07-10 09:25:38