Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPAbZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17, p < 0.001], RFS [HR: 1.59; 95% CI 1.02–2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49, p = 0.020]). In summary, UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.
编码上游结合转录因子的UBTF基因串联重复突变（UBTF-TDs）近期在儿童急性髓系白血病（AML）患者中被报道，并被发现与特定遗传特征（8号染色体三体（+8）、FLT3内部串联重复（FLT3-ITD）、WT1突变）及不良预后相关。由于对成人AML中UBTF-TDs的认知有限，我们采用高分辨率片段分析技术对4247例新诊断的成人AML及高危骨髓增生异常综合征（MDS）患者进行了筛查。UBTF-TDs总体罕见（52/4247例，1.2%），但在年轻患者（中位年龄41岁）中显著富集，且与MDS相关形态学特征、显著更低的血红蛋白和血小板水平相关。UBTF-TDs患者同时伴有更高频率的+8（34% vs. 9%）、WT1（52% vs. 7%）和FLT3-ITD（50% vs. 20.8%）共突变，而与NPM1突变、CEBPA bZIP框内突变及t(8;21)等类别定义性病变相互排斥。基于检测到的高变异等位基因频率以及所有分析的复发患者（5例）均保留UBTF-TD突变的事实，UBTF-TDs代表早期克隆事件并在疾病过程中保持稳定。单变量分析显示，在整个队列中UBTF-TDs并非总生存期或无复发生存期的显著影响因素。然而，在占UBTF突变患者大多数的50岁以下患者中，UBTF-TDs是无事件生存期（EFS）、无复发生存期（RFS）和总生存期（OS）的不良独立预后因素，这一结论在多变量分析（纳入年龄、ELN2022遗传风险组等既定风险因素）中得到证实（EFS[HR: 2.20; 95% CI 1.52–3.17, p<0.001]、RFS[HR: 1.59; 95% CI 1.02–2.46, p=0.039]、OS[HR: 1.64; 95% CI 1.08–2.49, p=0.020]）。总之，UBTF-TDs不仅代表儿童AML中的新型类别定义性病变，在年轻成人患者中同样如此，且与骨髓增生异常特征及不良预后相关。
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