Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia
Menée à partir du séquençage de l'ADN et de l'ARN de fibroblastes issus d'échantillons de moelle osseuse prélevés sur 28 enfants atteints d'une leucémie myéloïde aiguë pour laquelle une chimiothérapie d'induction et une chimiothérapie de première ligne se sont avérées inefficaces, cette étude compare le génotype des patients avant et après le traitement d'induction afin d'identifier des mécanismes génétiques associés à la résistance thérapeutique
Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.
Leukemia , résumé, 2019