TCL1A polymorphism predicts AML progression in myeloid neoplasms

Variable risks of acute myeloid leukemia (AML) progression of myeloid malignancies are dependent upon their mutational and clinical features. A common TCL1A gene promoter polymorphism (rs2887399-T allele, G/T or T/T) reduces TCL1A expression and fitness for expansion of TCL1A-linked mutations recurrently found in MDS and CMML (TET2, ASXL1, SF3B1, SRSF2, IDH1/2, JAK2) compared to those with the G/G-allele (wild type). We analyzed 208 MDS and CMML patients who underwent targeted next generation sequencing of myeloid malignancy genes and rs2887399 genotyping. Primary analysis for evaluating AML-progression-free survival (PFS) and the cumulative incidence of AML progression compared patients with TCL1A-linked mutations plus the rs2887399-T allele to those with these mutations plus the wild type rs2887399-G/G genotype. Among patients with TCL1A-linked mutations (119/208, 57%), rs2887399-T carriers (n = 35) had lower 3-year AML progression (2.9% vs 18%, p = .037), longer AML PFS (96.4% vs 79.8%, P = .039) and lower cumulative incidence of AML (2.9% vs 17.3%, P = .006) than G/G carriers (n = 84), despite similar molecular risk. Multivariable Cox analysis showed reduced AML progression hazard in TCL1A-linked rs2887399-T carriers versus the TCL1A-linked-G/G and non-TCL1A-linked-T (HR 0.26, 95% CI 0.06-0.88, p=0.029). In conclusion, the rs2887399-T allele diminished and delayed AML evolution in MDS/CMML patients with TCL1A-linked mutations. These data support the concept that the TCL1A polymorphism in the setting of specific somatic mutations is a modulator of leukemogenesis, providing potential utility of such germline genotyping for disease risk stratification.