TCL1A polymorphism predicts AML progression in myeloid neoplasms

Abstract Background: Clonal hematopoiesis is driven by somatic mutations in hematopoietic stem cells that confer their fitness advantage and is associated with an increased risk of myeloid malignancies and other age-related diseases. Recent studies have identified a common polymorphism in the promoter of the gene TCL1A (rs2887399) associated with risk of mutations in TET2, ASXL1, SF3B1, SRSF2, IDH1/2, and JAK2 (hereafter referred to as TCL1A-linked mutations), but not DNMT3A (Weinstock, Gopakumar et al, Nature 2023). Those carrying the T-allele at this locus had reduced growth rate and prevalence of TCL1A-linked mutations compared to those with the G-allele (wildtype), and this is thought to be due to reduced expression of TCL1A in mutant hematopoietic stem cells in carriers of the T-allele. However, the impact of this polymorphism on AML progression in established myeloid neoplasms such as myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) is unknown. We hypothesized that patients (pts) with MDS or CMML who had TCL1A-linked mutations and rs2887399-T would show longer time to AML progression. Methods: We analyzed 186 adult pts (150 MDS, 36 CMML) diagnosed between 1994 and 2022 evaluated at the Stanford MDS Center between 2018 and 2023. Pts had an internal next-generation sequencing (NGS) panel targeting 164 genes relevant to myeloid malignancies; only pathogenic variants from the earliest NGS test were included. Genotyping at rs2887399 was performed using the ThermoFisher TaqMan qPCR SNP assay (Assay ID: C__15842295_20). This assay identified three possible genotypes: G/G. G/T, and T/T. Those carrying one or two copies of rs2887399-T were grouped together due to sample size limitations. Pts were stratified into four groups based on having TCL1A-linked mutations and rs2887399-T status. Treatment response (ORR) to HMAs was assessed (2023 IWG criteria). Kaplan-Meier curves and log rank statistics assessed overall survival (OS), progression-free survival (PFS), and AML PFS. Cox regression analysis evaluated AML progression adjusting for IPSS-M score, age, sex, MDS vs CMML, primary vs treatment-related status, hematopoietic cell transplantation and genotype. Results: Of the 186 pts, 90% had primary rather than therapy-related disease. The cohort was 63% male, with a median age of 72 yrs (range, 66–79). 23 pts (12.4%) (18 MDS, 5 CMML) had TCL1A-linked mutations and rs2887399-T, while 77 (41%) had TCL1A-linked mutations without rs2887399-T. Pts with TCL1A-linked mutations and rs2887399-T had a lower rate of AML progression compared to the remainder of the pts (4.3% vs 21%, n=23 vs 163, p = 0.05) and vs those with TCL1A-linked mutations who did not have rs2887399-T (4.3% vs. 25%, p = 0.038). At 3 years, AML PFS was 100% in pts with TCL1A-linked mutations and rs2887399-T, compared to 85% for the remainder of the pts (p<0.001). Univariate Cox proportional hazard modeling revealed a favorable although nonsignificant HR for this former group vs the remainder (HR 0.20, 95% CI: 0.03–1.45, p = 0.112). Notably, IPSS-M status was similar for these pt groups (medians, -0.19 vs -0.11, p = 0.6). Ten of the 23 rs2887399-T carriers received HMA treatment, with an ORR of 50%; only one of these pts progressed to AML. A distinctly lower but nonsignificant AML progression incidence was observed in TCL1A-linked mutation carriers who had rs2887399-T compared to those with the T allele in non-TCL1A-linked mutation pts (4.3% vs. 22%, n=23 vs 36, p = 0.077). In multivariable Cox regression analysis, older age (HR 1.06, 95% CI: 1.01–1.12, p = 0.022) and higher IPSS-M (HR 1.39, 95% CI: 1.01–1.74, p = 0.005) were significantly associated with increased risk of AML progression, whereas having a TCL1A-linked mutation and rs2887399-T maintained a protective trend (HR 0.27, 95% CI: 0.03–2.25, p = 0.2). Conclusion: In our cohort of MDS and CMML pts, the presence of rs2887399-T had a significantly lower rate of AML progression among pts harboring TCL1A-linked driver mutations. As rs2887399-T results in lower levels of TCL1A expression in mutant hematopoietic progenitor cells, these findings support a role for TCL1A expression as a risk factor for AML progression. Furthermore, rs2887399 genotype could inform risk stratification and therapeutic decision-making in these disorders. Further studies in larger, prospective cohorts are warranted to validate these findings and explore the mechanistic basis of TCL1A-mediated clonal modification.