Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
New York Genome Center, New York, NY, USA.
Leukemia. 2019 Aug;33(8):1934-1943. doi: 10.1038/s41375-019-0402-3. Epub 2019 Feb 13.
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.
急性髓系白血病（AML）的特征是抑癌基因和癌基因的突变，涉及成人和儿童中不同的基因。虽然某些突变与 AML 复发风险增加有关，但原发性化疗耐药 AML 的基因组景观尚未得到很好的定义。作为 TARGET 计划的一部分，我们对诱导化疗失败的儿科 AML 进行了全基因组 DNA 和转录组 RNA 和 miRNA 测序分析。我们确定了至少有三种具有诱导失败的患者遗传群体，包括存在 NUP98 重排、WT1 体细胞突变而无明显 NUP98 突变的患者，以及其他复发性变异，包括 KMT2C 和 MLLT10。化疗前后标本的比较揭示了截然不同且不变的基因表达谱。虽然这些白血病表现出明显的治疗耐药性，但在化疗暴露后仍表现出多种形式的克隆进化。这包括 FRMD8、DHX32、PIK3R1、SHANK3、MKLN1 突变等位基因的选择，以及 WT1 和 TP53 突变克隆的持续存在，以及 FLT3、PTPN11 和 NRAS 突变克隆的消除。这些发现描绘了儿科 AML 原发性化疗耐药的遗传机制，这应该为其诊断和治疗提供更好的方法。
