Comparison of the Clinicopathological Findings of Patients with SF3B1/JAK2, SF3B1/Calr, or SF3B1/MPL co-Mutations
Authors: Shao Richard , Zhang Hailing , Moscinski Lynn C. , Hussaini Mohammad Omar , Li Julie , Arfa Ahmed , Wang Le , Song Jinming 
Published: December 2024

Introduction
Philadelphia-negative myeloproliferative neoplasms (MPNs), including primary myelofibrosis (PMF) and polycythemia vera (PV) and essential thrombocythemia (ET), are hematologic disorders that most commonly harbor driver mutations in JAK2, CALR, or MPL. JAK2 is the most mutated gene in MPNs, followed by CALR and MPL. Patients with mutated CALR or MPL genes are reported to have a more favorable outcome than those with JAK2 mutations. However, these mutations are uncommon in myelodysplastic syndrome (MDS).
SF3B1 mutations, commonly detected in MDS, also occur in rare cases of MPN (more frequently in PMF or fibrotic stage of PV or ET) and in some patients with MDS/MPN, where they coexist with JAK2, CALR, or MPL mutations, particularly in MDS/MPN with SF3B1 mutations and thrombocytosis (MDS/MPN-SF3B1-T). So far, the prognostic significance of SF3B1 mutations in MPNs remains unclear.
Studies investigating clinicopathological differences among patients harboring SF3B1/JAK2, SF3B1/CALR, or SF3B1/CALR co-mutations are scarce, motivating our current investigation. Our study represents one of the largest cohort to date, comprising 151 patients with these specific co-mutations.
Methods
This study was approved by institute IRB protocol. All the patients with SF3B1/JAK2, SF3B1/CALR, or SF3B1/MPL co-mutations were identified from Next Generation Sequencing (NGS) database (a 96 gene panel). Patient demographics and cytogenetic data were retrieved from the EMR. Morphologic diagnosis was confirmed by two hematopathologists. Overall survival was calculated from the sequencing date to the death or last follow-up date.
Scientific data analysis included Fisher's exact test for categorical variables, the Mann-Whitney U-test for numerical variables, and Kaplan-Meier analysis for survival curve assessments.
Results
A total of 151 patients were included in this study, comprising of 110 with SF3B1/JAK2, 19 with SF2B1/CALR, and 22 with SF3B1/MPL co-mutations. These co-mutations were observed without statistically significant difference in occurrence across MPN, MDS/MPN, acute myeloid leukemia (AML), or PMF, PV, ET, MDS/MPN-SF3B1-T. SF3B1/CALR co-mutations were more frequent in MDS (p=0.0145), while SF3B1/MPL mutations were associated with a higher likelihood of leukopenia (p=0.0455). TET2 and ASXL1 mutations were frequently associated with these co-mutations. SRSF2 mutations were more commonly found in conjunction with SF3B1/MPL (p &lt; 0.05), and PPM1D mutations were more frequently associated with SF3B1/CALR (p=0.0207) co-mutations. Co-mutation rates with other genes, including TP53, were similar across MDS, MDS/MPN and MPN. Factors such as age, gender, hemoglobin level, platelet count, median survival time, or overall survival, bone marrow cellularity, bone marrow blast percentage, bone marrow fibrosis, and cytogenetic profiles (with normal karyotype being the most common) did not show significant differences among these co-mutation groups.
Discussion
In our study, SF3B1 was found to co-mutate with JAK2, CALR, or MPL in a spectrum of myeloid neoplasms with similar frequencies, except that SF3B1/CALR were more frequent in MDS than the other co-mutations. Prior studies revealed age differences in MPN patients with JAK2 and CALR mutations, but we found no significant age differences when co-mutated with SF3B1. Gender distribution in prior studies showed a higher prevalence of females with JAK2 mutation versus CALR in MPN, while there is no significant difference when co-mutated with SF3B1 in our study. Other studies associated CALR mutations with reduced likelihood of moderate-to-severe anemia, thrombocytopenia, or leukocytosis when compared to JAK2-mutated patients in MPN, which we did not observe in patients with co-mutated SF3B1. Furthermore, other studies have reported that JAK2 mutations are linked to shorter overall survival and leukemia-free survival compared to CALR mutations in MPN, which we did not find in patients with co-mutated SF3B1.
Conclusion
SF3B1/JAK2, SF3B1/CALR, SF3B1/MPL co-mutations are observed in MDS, MPN, MDS/MPN, or AML with no significant difference in overall survival time. These co-mutations exhibit similar, but slightly different clinicopathological presentations compared to patients without SF3B1 co-mutations reported by other studies. However, the larger cohort study might be necessary to confirm these findings.