Characterisation and prognostic impact Of ZRSR2 mutations in myeloid neoplasms

The ZRSR2 gene, located on the X chromosome (Xp22.1),is a member of the RNA splicing machinery family of genes which also includes SF3B1, SRSF2, and U2AF1 1-3.Spliceosome gene mutations are found in 35% of myelodysplastic syndrome (MDS) patients and were described as being mutually exclusive with each other 3,4.ZRSR2m is seen in 4% of MDS, and across different myeloid neoplasms (MN) including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasm (MPN) 1,[567.Damm et al. found that mutations in ZRSR2 were evenly distributed across the entire gene, and included nonsense, frameshift, and splice site mutations 1,2.The only co-mutation that showed significant association with ZRSR2 was TET2 (p < 0.001) 2,8,9.ZRSR2m cells showed increased precursor cells for macrophages and decreased precursor cells for erythroid cells 10.Malcovati et al. reported that TET2, ZRSR2 co-mutation was predictive of myelomonocytic phenotype and showed higher hemoglobin (Hgb) levels and monocyte counts 11.This is a retrospective study done with IRB approval at our institution.No interaction was done with patients.A waiver of consent was approved by our IRB due to minimal risk nature.No cases of age younger than 18 were included.This study was conducted in a single institution.All methods carried out in our study were in accordance with relevant guidelines and regulations.Next-generation sequencing (NGS) was performed in the molecular hematopathology laboratory with the NGS gene panel including 42-47 genes, between 2016-2023.BlueSky Statistics V10.3.1 was used for data analysis.NGS was performed clinically on 9320 samples, 164 had the ZRSR2m genotype, with only 2 being female (1.2%).Median patient age was 74 (range 31-92).The most common diagnosis was MDS (n = 53, 32.3%), clonal cytopenia of undetermined significance (CCUS) (n = 39, 23.8%), MPN (n = 33, 20.1%), MDS/ MPN overlap (n = 23, 14%), AML (n = 15, 9.1%) and 1 mixed phenotype acute leukemia (MPAL).Fifteen (9%) patients had concurrent non-myeloid hematological malignancies diagnosed at