Clinical characteristics and prognostic significance of co-mutated SETBP1/GATA2 myeloid neoplasms

SETBP1 gene, located on 18q12.3, is a major oncogene in myeloid neoplasms. GATA2 gene, located on 3q21, is one of the six GATA transcription factors regulating gene expression via two conserved zinc finger domains (ZF). Previous data suggested that in patients with germline GATA2 mutation (m), acquisition of a somatic SETBP1 mutation (m) was associated with leukemic transformation among patients with AML, excess blast MDS and CMML. We hypothesize that the co-occurrence of SETBP1m and GATA2m have a unique impact on the clinical and molecular characteristics of myeloid neoplasms. After IRB approval, we retrospectively reviewed the charts of patients who had myeloid NGS panel results between 2016 and 2023. All patients with myeloid neoplasms who had either SETBP1m or GATA2m were included. One hundred sixty-eight patients had either SETBP1m and/or GATA2m; 105 patients had SETBP1m, 54 had GATA2m and 9 had both SETBP1m and GATA2m. Majority (66.1 %) were males with a median age of 71.3 years. At time of NGS, MDS/MPN was the most common diagnosis (32.1 %), followed by MDS (30 %) and AML (20.2 %). In SETBP1m/GATA2m patients, 7 GATA2m clustered in zinc finger 2 (ZF2) (77.8 %); higher than the ZF2 mutated cases among SETBP1wt/GATA2m (46.3 %, p = 0.1). Among SETBP1m/GATA2m, 77.8 % of patients had SRSF2 co-mutation, compared to 44.8 % among SETBP1m/GATA2wt (p = 0.08), and 27.8 % among SETBP1wt/GATA2m (p = 0.006). AML progression frequency for non-AML cases did not significantly differ between the 3 groups. Survival of SETBP1m/GATA2m patients was not worse compared to SETBP1wt/GATA2m or SETBP1m/GATA2wt.