PT  - JOURNAL ARTICLE
AU  - Nicole A. McNeer
AU  - John Philip
AU  - Heather Geiger
AU  - Rhonda E. Ries
AU  - Vincent-Philippe Lavallée
AU  - Michael Walsh
AU  - Minita Shah
AU  - Kanika Arora
AU  - Anne-Katrin Emde
AU  - Nicolas Robine
AU  - Todd A Alonzo
AU  - E. Anders Kolb
AU  - Alan S Gamis
AU  - Malcolm Smith
AU  - Daniela Se Gerhard
AU  - Jaime Guidry-Auvil
AU  - Soheil Meshinchi
AU  - Alex Kentsis
TI  - Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia: A report from the TARGET initiative
AID  - 10.1101/475376
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 475376
4099  - http://biorxiv.org/content/early/2018/11/26/475376.short
4100  - http://biorxiv.org/content/early/2018/11/26/475376.full
AB  - 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 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 or contraction 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.