Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy

Abstract

Key Points• Two distinct evolutionary patterns govern early and late relapse.• Evolutionary patterns suggest a mutationdriven resistance for early relapses and a reexpansion of dormant cells for late ones.Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer.Refractory/relapsed cALL presents a survival rate of ;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 postdiagnosis) from late relapse events remain elusive. Here, we use an integrative genome-based analysis combined with serial sampling of relapsed tumors (from primary tumor to #4 relapse events) from 19 pre-B-cell 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 2 distinct evolutionary patterns govern early and 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.

Global efforts toward the cure of childhood acute lymphoblastic leukaemia

“…In ETV6-RUNX1 ALL, there is a striking over-representation of RAG-mediated genomic mutational process 59 , plausibly linked to inflammation/infection-related activation of these recombination events 60 . In contrast, leukemia evolution plays a completely different role during ALL therapy, often times as a primary means of evasion of cytotoxic effects of chemotherapy 61 . Somatic mutations in key drug targets of metabolizing genes (e.g., NT5C2 and PRPS1) have been identified specifically at the time of ALL relapse and are shown to confer dramatic resistance to anti-leukemic agents 62,63,64 .…”

Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations

“…Previous studies have used allele frequency (AF) thresholds to define mutations as being present in a minor subclonal or major clone (clonal) ranging between 20% and 30% [5][6][7][8] . In this study, we used an AF threshold of 25% to separate major clonal from subclonal alterations, since mutations below 25%…”

Single-cell analysis of childhood leukemia reveals a link between developmental states and ribosomal protein expression as a source of intra-individual heterogeneity

“…Another study found the presence of at least two distinct genetic subclones in five out of six patients using targeted single-cell DNA sequencing 9 . In this context, we reported different clonal dynamics between early (during treatment) and late (>36 months after diagnostic) bone marrow relapse events and showed variable clonal origin in late relapse events 10 .…”