Genomic and Transcriptomic Differences of Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) and Myelodysplastic Syndrome with Ring Sideroblasts (MDS-RS)

INTRODUCTION: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare hematological disorder characterized by anemia, bone marrow dysplasia with ring sideroblasts and persistent thrombocytosis, and high frequency of SF3B1 and JAK2 mutations. Despite clinical, histological and molecular similarities with MDS with ring sideroblasts (MDS-RS), the clinical outcomes of these entities are diverse. To date, there is no data evaluating specific functional pathways which might explain phenotypic and clinical differences beyond diverse frequencies of JAK2 mutation. METHODS: We evaluated a total of 24 patients (pts) with MDS/MPN-RS-T and 27 pts with MDS-RS. Diagnosis was based on WHO 2017 criteria and confirmed by two independent hematopathologists. Whole bone marrow DNA was subject to 81 gene targeted next-generation sequencing (NGS) analysis. CD34+ cells from bone marrow samples of 4 pts with MDS/MPN-RS-T, 7 pts with MDS-RS and 17 healthy individuals obtained from AllCells (Emeryville, CA) were isolated using the CD34 MicroBead Kit and RNA was isolated using the PicoPure RNA isolation kit. Fastq files were mapped to the human genome (build GRCh38) in TopHat2 using the default options. Differential gene expression analysis was conducted using DESeq2 in R version 3.6.2. Pathway enrichment analysis was performed using gene set enrichment analysis, with the fgsea library in R. RESULTS: Patients with MDS/MPN-RS-T had higher median bone marrow ring sideroblast percentage (47% vs 32%, p=0.04) and absolute neutrophil count (4.34x109/L vs 2.99x109/L, p=0.001). Frequency of identified mutations and their VAFs compared to MDS-RS are shown in Figure 1A. The median number of mutations was higher in MDS/MPN-RS-T than in MDS-RS (3 vs 2, p CONCLUSIONS: MDS/MPN-RS-T is characterized by co-dominance of SF3B1 and JAK2 mutations and presence of minor kinase signaling mutations not observed in MDS-RS. Upregulation of cytokine and interleukin signaling mediated through GPC receptors, and downregulation of genes involved in apoptosis and DNA damage are unique transcriptomic features of MDS/MPN-RS-T likely driven by genotype. These unique genomic and transcriptomic characteristics of MDS/MPN-RS-T supports the classification of MDS/MPN-RS-T based on genomic features beyond presence of SF3B1 mutation, and might represent potential therapeutic avenues for this rare disease. Download : Download high-res image (414KB) Download : Download full-size image Figure . Disclosures Sasaki: Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Kantarjian: Sanofi: Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BioAscend: Honoraria; Novartis: Honoraria, Research Funding; Delta Fly: Honoraria; Pfizer: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Ascentage: Research Funding. Garcia-Manero: Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy.