Mutational dynamics of early and late relapsed cALL: rapid clonal expansion and long-term dormancy. Homo sapiens

Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer. Refractory/ relapse cALL presents a survival rate of about 45% and is still one of the leading causes of death by disease among children. Mechanisms such as clonal competition and evolutionary adaptation govern treatment resistance. However, the underlying clonal dynamics leading to multiple relapses and differentiating early (<36 months post-diagnosis) from late relapse events remains elusive. Here, we use an integrative genome-based analysis combined to serial sampling of relapsed tumors (from primary tumor to up to four relapses events) from 19 pre-B cALL patients (8 early and 11 late relapses) to assess the fitness of somatic mutations and infer their ancestral relationships. By quantifying both general clonal dynamics and newly acquired subclonal diversity, we show that two distinct evolutionary patterns govern either early or late relapse: on one hand a highly dynamic pattern, sustained by a putative defect of DNA repair processes, illustrating the quick emergence of fitter clones - and on the other hand, a quasi-inert evolution pattern suggesting the escape from dormancy of leukemia stem cells likely spared from initial cytoreductive therapy. These results offer new insights into cALL relapse mechanisms and highlight the pressing need for adapted treatment strategies to circumvent resistance mechanisms.