DNA methyltransferase 3 A mutations (DNMT3AMT) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3AMT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3AMT identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3AMT hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3AMT more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3AMT. When the sum of variant allele frequencies (VAFs) for multiple DNMT3AMT exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P < 0.0001) suggesting that they occurred in biallelic configuration. AML patients with biallelic DNMT3A inactivation (n = 52) presented with older age (P = 0.029), higher leukocytes (P < 0.0001) and peripheral blast counts (P = 0.0001) and significantly poorer survival rate (5.6% vs. 47.6% at 2 years; P = 0.002) than monoallelic DNMT3AMT. Multivariate analysis identified biallelic DNMT3AMT (HR 2.65; P = 0.001), male gender (HR 2.05; P = 0.014) and adverse genetic alteration according to the European LeukemiaNet 2022 classification (HR 1.84; P = 0.028) as independent adverse factors for survival, whereas intensive chemotherapy (HR 0.47; P = 0.011) favorably influenced outcomes. Longitudinal molecular analysis of 12 cases with biallelic DNMT3AMT demonstrated that such clones persisted or expanded in 9 relapsed or transformed cases (75%) suggesting the early origin of biallelic hits with strong leukemogenic potential. Our study describes the likelihood that biallelic DNMT3AMT, while rare, are indeed compatible with clonal expansion and thus questions the applicability of synthetic lethality strategies.

中文翻译：

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双等位基因 DNMT3A 突变骨髓肿瘤的景观


DNA 甲基转移酶 3 A 突变 (DNMT3AMT) 在骨髓瘤 (MN) 中很常见，并且大多是杂合的。然而，也可能遇到具有多个 DNMT3AMT 的病例，但其临床和遗传状况仍未得到探索。我们回顾性分析了 5,603 个连续 MN 中识别出的 533 个 DNMT3AMT 病例，其中 8.4% 具有多次 DNMT3AMT 命中。它们在急性髓系白血病 (AML) 中最常见，其中 R882 变异占多次命中的 13.3%。与具有单个 DNMT3AMT 的患者相比，多个 DNMT3AMT 更可能与 IDH2 (P = 0.005) 和 ETV6 (P = 0.044) 突变同时发生。当多个 DNMT3AMT 的变异等位基因频率 (VAF) 总和超过 60% 时，我们发现两个 DNMT3A 变异之间存在显着的正克隆负担相关性 (P < 0.0001)，表明它们以双等位基因构型发生。双等位基因 DNMT3A 失活的 AML 患者 (n = 52) 年龄较大 (P = 0.029)、白细胞计数较高 (P < 0.0001) 和外周原始细胞计数 (P = 0.0001)，且生存率显着较差（5.6% vs. 47.6%） 2 年时；P = 0.002) 优于单等位基因 DNMT3AMT。多变量分析确定双等位基因 DNMT3AMT（HR 2.65；P = 0.001）、男性（HR 2.05；P = 0.014）和根据欧洲 LeukemiaNet 2022 分类的不良基因改变（HR 1.84；P = 0.028）作为生存的独立不利因素，而强化化疗（HR 0.47；P = 0.011）对结果有有利影响。对 12 例双等位基因 DNMT3AMT 病例的纵向分子分析表明，此类克隆在 9 例复发或转化病例 (75%) 中持续存在或扩增，表明具有强致白血病潜力的双等位基因命中的早期起源。 我们的研究描述了双等位基因 DNMT3AMT 虽然罕见，但确实与克隆扩增兼容的可能性，因此对合成致死策略的适用性提出了质疑。