Genetic Mechanisms Of Primary Chemotherapy Resistance In Pediatric Acute Myeloid Leukemia: A Report From The Target Initiative

Acute myeloid leukemias (AML) are characterized by distinct 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 sequencing, transcriptome RNA, and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified three distinct genetic groups of patients with induction failure, including those with <em>NUP98</em> rearrangements, somatic mutations of <em>WT1</em>, <em>ELF1</em>, <em>KMT2C</em>, <em>MLLT10,</em> and additional recurrent gene mutations, fusions, and structural rearrangements, some of which have been observed in other malignancies. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting gross therapy resistance, these leukemias had diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of <em>FRMD8</em>, <em>DHX32</em>, <em>PIK3R1</em>, <em>SHANK3</em>, <em>MKLN1</em>, as well as persistence of <em>WT1</em> and <em>TP53</em> mutant clones, and elimination or contraction of <em>FLT3</em>, <em>PTPN11</em>, and <em>NRAS</em> mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.