Clonal Evolution of Acute Myeloid Leukemia Revealed by High-Throughput Single-Cell Genomics

BioRxiv : the Preprint Server for Biology
Kiyomi MoritaKoichi Takahashi

Abstract

One of the pervasive features of cancer is the diversity of mutations found in malignant cells within the same tumor; a phenomenon called clonal diversity or intratumor heterogeneity. Clonal diversity allows tumors to adapt to the selective pressure of treatment and likely contributes to the development of treatment resistance and cancer recurrence. Thus, the ability to precisely delineate the clonal substructure of a tumor, including the evolutionary history of its development and the co-occurrence of its mutations, is necessary to understand and overcome treatment resistance. However, DNA sequencing of bulk tumor samples cannot accurately resolve complex clonal architectures. Here, we performed high-throughput single-cell DNA sequencing to quantitatively assess the clonal architecture of acute myeloid leukemia (AML). We sequenced a total of 556,951 cells from 77 patients with AML for 19 genes known to be recurrently mutated in AML. The data revealed clonal relationship among AML driver mutations and identified mutations that often co-occurred (e.g., NPM1/FLT3-ITD, DNMT3A/NPM1, SRSF2/IDH2, and WT1/FLT3-ITD ) and those that were mutually exclusive (e.g., NRAS/KRAS, FLT3 -D835/ITD, and IDH1/IDH2 ) at single-cell resolution. Reco...Continue Reading

Related Concepts

Malignant Neoplasms
Biological Evolution
Genes
Leukemia, Myelocytic, Acute
N-ras Genes
Neoplasms
FLT3 protein, human
Medical History
Tumor Cells, Malignant
Convergence - Direction

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