Epigenetic dysregulation of the polycomb axis in Acute Myeloid Leukemia: Clinical and prognostic correlates

Abstract Background Epigenetic regulation of gene expression is a complex biological process. Polycomb Repressive Complex (PCR) 1 0.05). ASXL-1 mt AML had similar CCR rates (45% vs 54%, P=0.1)MV-LR: odds ratio (OR) 0.69, 95CI 0.31-1.13, median OS (12 vs 8 months (mo))MV-CPH: hazard ratio (HR) 1.2, 95CI 0.92-1.54 and median EFS (5.7 vs 7.8 mo)MV-CPH: HR 1.17, 95CI 0.91-1.5 to ASXL-1 wt AML. Compared to BCOR wt AML, patients with BCOR mt AML were older (average 69 vs 65 years) and had lower total WBCs (3 vs 7 K/μL) but higher platelets (68 vs 50 K/μL) at presentation (all P0.05). The CCR rate was similar in BCOR mt and wt (48% vs. 53%, P=0.5)(MR-LR: OR 0.88, 95CI 0.46-1.67). There was no difference in median OS (14 vs 11 mo, P=0.4)MV-CPH: HR 0.8, 95%CI 0.56-1.13 or EFS (8.9 vs 7 mo, P=0.9)MR-CPH: HR 0.87, 95CI: 0.62-1.21 in the BCOR mt and wt AML, respectively. Patients with EED mt AML were less likely to be white (60% vs 90%) compared to patients with EED wt AML (P0.05). Patients with EED mt AML had similar CCR rate (100% vs. 51%)(P=0.12), median OS (16 vs 12 mo)MV-CPH: HR 2, 95CI 0.73-5.47, and median EFS (8.6 vs 7.6 mo)MV-CPH: HR 1.81, 95CI 0.66-4.95 to EED wt AML. Patients with EZH2 mt AML were older (69 vs 66 years) and had lower blasts at presentation (25% vs 50%) compared to patients with EZH2 wt AML (P0.05). There was no difference in CCR rate (48% vs 53%, P=0.6)MV-LR: OR 0.92, 95CI 0.39-2.11, median OS (11 vs 12 mo)MV-CPH: HR 1, 95CI 0.66-1.51 or median EFS (5.1 vs. 7.4 mo)MV-CPH: HR 0.99, 95CI 0.66-1.5 between EZH2 mt and wt AML, respectively. Patients with KDM6A mt AML exhibited a clinical presentation comparable to those with wt KDM6A. Patients with KDM6A-mt and wt had similar CCR (70% vs 52%, P=0.3)MV-LR: OR 2.8, 95CI 0.5-21.8, median OS (7.3 vs 12 mo)MV-CPH: HR 1.67, 95CI 0.68-4.12 and median EFS (7.3 vs 7.6 mo)MV-CPH HR: 1.34, 95CI 0.55-3.30. Lastly, patients with SUZ12 mt AML had a similar clinical presentation to patients with SUZ12 wt AML. Patients with SUZ12 mt AML had higher CCR rate (80% vs. 51%, P=0.11)MV-LR: OR 5.33, 95CI 1.18-38.2, similar median OS (17 vs 11 mo)MV-CPH: HR 0.29, 95CI 0.07-1.19, and similar median EFS (13 vs 7.1 mo)MV-CPH: HR 0.51, 95CI 0.16-1.61. Conclusion: Mutations in the PRC axis are common in AML, and individual mutations often exhibit distinct clinicopathological features. Although ASXL1, BCOR & EZH2 are categorized as high-risk mutations in the 2022 European LeukemiaNet classification, our analysis found no significant association between these mutations and treatment response or OS. Interestingly, SUZ12 mutations were associated with a higher treatment response rate and a numerically longer median survival, suggesting a potentially favorable prognosis. Large multi-institutional studies are needed to better elucidate the prognostic relevance of PRC-axis mutations, particularly in rare molecular subtypes of AML.