Zhang, Ling

Abstract Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.

Abstract Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) 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 TN-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. Significance: This study establishes that MYC expression is increased in TN-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 TN-MPNs.

Abstract Myelodysplastic neoplasms (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Accurate pathologic diagnoses present challenges because of interobserver variability in interpreting morphology and quantifying dysplasia. We compared local clinical site diagnoses with central, adjudicated review from 918 participants enrolled in the ongoing National Heart, Lung, and Blood Institute National MDS Natural History Study, a prospective observational cohort study of participants with suspected MDS or MDS/myeloproliferative neoplasms (MPNs). Locally, 264 (29%) were diagnosed as having MDS, 15 (2%) MDS/MPN overlap, 62 (7%) idiopathic cytopenia of undetermined significance (ICUS), 0 (0%) acute myeloid leukemia (AML) with <30% blasts, and 577 (63%) as other. Approximately one-third of cases were reclassified after central review, with 266 (29%) diagnosed as MDS, 45 (5%) MDS/MPN overlap, 49 (5%) ICUS, 15 (2%) AML with <30%, and 543 (59%) as other. Site miscoding errors accounted for more than half (53%) of the local misdiagnoses, leaving a true misdiagnosis rate of 15% overall, 21% for MDS. Therapies were reported in 37% of patients, including 43% of patients with MDS, 49% of patients with MDS/MPN, and 86% of patients with AML with <30% blasts. Treatment rates were lower (25%) in cases with true discordance in diagnosis compared with those for whom local and central diagnoses agreed (40%), and receipt of inappropriate therapy occurred in 7% of misdiagnosed cases. Discordant diagnoses were frequent, which has implications for the accuracy of study-related and national registries and can lead to inappropriate therapy. This trial was registered at www.clinicaltrials.gov as #NCT05074550.