Background Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. Results We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 10 8 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. Conclusions The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse.

中文翻译：

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成人T细胞急性淋巴细胞白血病复发的演变

背景 成人 T 细胞急性淋巴细胞白血病 (T-ALL) 是一种罕见疾病，每百万人中只有不到 10 人受到影响。与更为普遍的同源儿科恶性肿瘤相比，对它的研究较少。与儿童相比，成年患者复发的比例更高。因此，有必要研究成人 T-ALL 病例的复发机制。结果 我们分析了 19 例成年患者原发性 T-ALL 和相应的复发恶性肿瘤的全基因组体细胞突变，并与 238 例儿童和年轻成人 ALL 病例进行比较，分析了它们在治疗后的演变。我们将原发性和复发性成人 T-ALL 与儿科患者的突变过程和驱动突变进行了比较。对白血病细胞中时钟样突变的精确估计表明，复发克隆的出现发生在原发性 T-ALL 诊断前几个月。具体来说，通过白血病群体的倍增时间，我们发现在19名患者中至少有14名患者中，诊断时存在的复发性白血病群体包含多于1个但少于10 8 个原始细胞。通过模拟，我们发现所有患者的复发似乎都是由基因突变引起的。结论 成人 T-ALL 病例中早期出现的具有遗传耐药机制的白血病细胞群对治疗构成了挑战。因此，改善恶性肿瘤的早期发现是防止其复发的关键。