Genomic Landscape of Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Central Study

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with <i>TET2</i> (52%) being the most frequently mutated gene, followed by <i>ASXL1</i> (38.7%), <i>SRSF2</i> (34.7%), and <i>JAK2</i> (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., <i>TET2/SRSF2</i> in CMML, <i>ASXL1/SETBP1</i> in aCML, and <i>SF3B1/JAK2</i> in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in <i>RUNX1</i> and <i>TP53</i> were associated with poorer clinical outcomes in CMML (<i>p</i> < 0.05) by multivariate analysis. In MDS/MPN-U, <i>CBL</i> mutations (<i>p</i> < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (<i>p</i> < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.