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Myelodysplastic syndrome

Co-mutation pattern, clonal hierarchy, and clone size concur to determine disease phenotype of SRSF2P95-mutated neoplasms


Somatic mutations in splicing factor genes frequently occur in myeloid neoplasms. While SF3B1 mutations are associated with myelodysplastic syndromes (MDS) with ring sideroblasts, SRSF2P95 mutations are found in different disease categories, including MDS, myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). To identify molecular determinants of this phenotypic heterogeneity, we explored molecular and clinical features of a prospective cohort of 279 SRSF2P95-mutated cases selected from a population of 2663 patients with myeloid neoplasms. Median number of somatic mutations per subject was 3. Multivariate regression analysis showed associations between co-mutated genes and clinical phenotype, including JAK2 or MPL with myelofibrosis (OR = 26.9); TET2 with monocytosis (OR = 5.2); RAS-pathway genes with leukocytosis (OR = 5.1); and STAG2, RUNX1, or IDH1/2 with blast phenotype (MDS or AML) (OR = 3.4, 1.9, and 2.1, respectively). Within patients with SRSF2–JAK2 co-mutation, JAK2 dominance was invariably associated with clinical feature of MPN, whereas SRSF2 mutation was dominant in MDS/MPN. Within patients with SRSF2–TET2 co-mutation, clinical expressivity of monocytosis was positively associated with co-mutated clone size. This study provides evidence that co-mutation pattern, clone size, and hierarchy concur to determine clinical phenotype, tracing relevant genotype–phenotype associations across disease entities and giving insight on unaccountable clinical heterogeneity within current WHO classification categories.

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Fig. 1: Co-mutation plot for somatically mutated genes in SRSF2P95-mutated neoplasms.
Fig. 2: Associations between somatic mutations and clinical phenotype.
Fig. 3: Clinical phenotype of JAK2SRSF2-mutated myeloid neoplasms reflects the hierarchy of JAK2-mutated clone.
Fig. 4: Relationship between TET2–SRSF2 double-mutant clone and monocytosis.
Fig. 5: Relationship between WHO classification, co-mutation pattern, and clinical outcome in SRSF2-mutated neoplasms.


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This study was supported by Associazione Italiana per la Ricerca sul Cancro (Milan, Italy) through the International Accelerator Program (Early detection and intervention: Understanding the mechanisms of transformation and hidden resistance of incurable hematological malignancies, Project Code: 22796); the 5×1000 project “Actionable targets in clonal progression and systemic spreading of myeloid neoplasms,” (MYNERVA project, Project Code: 21267); and the Investigator Grant 2017 (Project Code: 20125). Additional support was provided by the Italian Ministry of Health for young researchers (GR-2016-02361272), the Italian Society of Hematology, American-Italian Cancer Foundation, the Swedish Cancer Society (Cancerfonden, 150269), the Cancer Research Foundations of Radiumhemmets (Radiumhemmets Forskningsfonder, 151103), the Swedish Research Council (Vetenskapsrådet, 521-2013-3577), the JSPS KAKENHI (JP15H05909 and JP19H05656), the Japanese Ministry of Education, Culture, Sports, Science and Technology (hp160219), and by AMED (JP19ck0106250h0003).

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GT, LM, and MCa designed the study, performed statistical analysis, and wrote the manuscript; AG, PG, YN, DP, and MD analyzed sequencing data; VR performed single-cell colony genotyping; EM and SC processed samples; MR and ERi performed bioinformatic analysis; GT, MCr, PG, ERu, CE, EB, and JU collected clinical data; AMV, SO, and EH-L contributed to study design and interpretation of the data.

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Correspondence to Luca Malcovati.

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Todisco, G., Creignou, M., Gallì, A. et al. Co-mutation pattern, clonal hierarchy, and clone size concur to determine disease phenotype of SRSF2P95-mutated neoplasms. Leukemia 35, 2371–2381 (2021).

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