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 & 2 repress gene expression through epigenetic chromatin modification. Mutations in PRC1/2 (e.g., BCOR, EED, EZH2 & SUZ12) and regulators of this axis (e.g., ASXL1 & KDM6A) are recurrently found in acute myeloid leukemia (AML). We aim to provide a comprehensive clinical and prognostic description of commonly mutated genes in the PRC axis and associated regulators. Methods We conducted a retrospective cohort study at our academic institution (1/2015 -9/2023) to evaluate the clinical presentation of prognostic significance of adult patients with AML harboring a mutation in ASXL1, BCOR, EED, EZH2, KDM6A, or SUZ12. We collected demographics, molecular profiles, cytogenetics, treatments administered, and outcomes on all patients. Mutations were determined by next-generation sequencing panels. Outcomes included composite complete response (CCR=CR + CRi), overall survival (OS), and event-free survival (EFS). Kaplan-Meier analysis and multivariable logistic (MV-LR) and Cox regression (MV-CPH) models were used, adjusting for age, cytogenetics, TP53 status, gender, and comorbidities. Results: During the study period, 971 patients with newly diagnosed AML (2016 and 2022 WHO) were treated at our center. The frequency of mutated genes in the PRC axis were ASXL1 (n=102/627, 16%), BCOR (n=60/625, 9.6%), EED (n=5/434, 1%), EZH2 (n=33/623, 5%), KDM6A (n=10/440, 2%), & SUZ12 (n=10/438, 2%). Compared to patients with ASXL1 wildtype (wt) AML, patients with ASXL1 mutated (mt) AML were older (average 69 vs 65 years) and more likely male (67% vs. 54%) (all P<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 P<0.05). 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 (P<0.05). 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 (P<0.05). 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.