We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the current study, we considered 179 U2AF1-mutated patients with clonal cytopenia of undetermined significance (CCUS; n = 22), MDS (n = 108), MDS/acute myeloid leukemia (AML; n = 18) and AML (n = 31). U2AF1 variants included S34 (60%), Q157 (35%), and others (5%): corresponding mutational frequencies were 45%, 55%, and 0% in CCUS; 57%, 39%, and 4% in MDS; 61%, 33%, and 6% in MDS/AML; and 55%, 35% and 10% in AML (P = 0.17, 0.36 and 0.09), respectively. Concurrent mutations included ASXL1 (37%), BCOR (19%), RUNX1 (14%), TET2 (15%), DNMT3A (10%), NRAS/KRAS (8%), TP53 (8%), JAK2 (5.5%) and SETBP1 (5%). The two most frequent U2AF1 MT were S34F (n = 97) and Q157P (n = 46); concurrent MT were more likely to be seen with the latter (91% vs 74%; P = 0.01) and abnormal karyotype with the former (70% vs 62%; P = 0.05). U2AF1 S34F MT clustered with BCOR (P = 0.04) and Q157P MT with ASXL1 (P = 0.01) and TP53 (P = 0.03). The median overall survival (OS) in months was significantly worse in AML (14.2) vs MDS/AML (27.3) vs MDS (33.7; P = 0.001); the latter had similar OS with CCUS (30.0). In morphologically high-risk disease (n = 49), defined by ≥10% blood or bone marrow blasts (i.e., AML or MDS/AML), median OS was 14.2 with Q157P vs 37.1 months in the presence of S34F (P = 0.008); transplant-adjusted multivariable analysis confirmed the detrimental impact of Q157P (P = 0.01) on survival and also identified JAK2 MT as an additional risk factor (P = 0.02). OS was favorably affected by allogeneic hematopoietic stem cell transplantation (HR: 0.16, 95% CI; 0.04-0.61, P = 0.007). The current study defines the prevalence and co-mutational profiles of U2AF1 pathogenic variants in AML, MDS/AML, MDS, and CCUS, and suggests prognostic heterogeneity in patients with ≥10% blasts.
我们既往已认识到U2AF1突变在骨髓纤维化及骨髓增生异常综合征中存在的基因型与预后异质性。本研究纳入了179例携带U2AF1突变的患者，包括意义未明的克隆性血细胞减少症22例、骨髓增生异常综合征108例、MDS/急性髓系白血病18例以及急性髓系白血病31例。U2AF1变异类型包括S34型（60%）、Q157型（35%）及其他（5%）；在CCUS、MDS、MDS/AML及AML中，相应突变频率分别为45%/55%/0%、57%/39%/4%、61%/33%/6%和55%/35%/10%（P值分别为0.17、0.36和0.09）。共现突变包括ASXL1（37%）、BCOR（19%）、RUNX1（14%）、TET2（15%）、DNMT3A（10%）、NRAS/KRAS（8%）、TP53（8%）、JAK2（5.5%）和SETBP1（5%）。最常见的两种U2AF1突变类型为S34F（97例）和Q157P（46例）；后者更易出现共现突变（91% vs 74%；P=0.01），前者更常伴有异常核型（70% vs 62%；P=0.05）。U2AF1 S34F突变与BCOR存在聚类关联（P=0.04），Q157P突变则与ASXL1（P=0.01）和TP53（P=0.03）相关。中位总生存期在AML（14.2个月）较MDS/AML（27.3个月）及MDS（33.7个月）显著缩短（P=0.001）；MDS与CCUS（30.0个月）的生存期相近。在形态学高危疾病（外周血或骨髓原始细胞≥10%的AML或MDS/AML，共49例）中，Q157P突变患者中位OS为14.2个月，而S34F突变患者为37.1个月（P=0.008）；经移植校正的多变量分析证实Q157P对生存具有不利影响（P=0.01），并识别JAK2突变为额外风险因素（P=0.02）。异基因造血干细胞移植可显著改善总生存期（风险比：0.16，95%置信区间：0.04-0.61，P=0.007）。本研究明确了U2AF1致病性变异在AML、MDS/AML、MDS及CCUS中的分布特征与共突变谱，并提示原始细胞≥10%的患者存在预后异质性。
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