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Abstract
For many years, immortalized tumor cell lines have been used as reliable tools to understand the function of oncogenes and tumor suppressor genes. Today, we know that tumors can comprise subclones with common and with subclone-specific genetic alterations. We sequenced DNA and RNA of sequential sister cell lines obtained from patients with pre-B acute lymphoblastic leukemia at different phases of the disease. All five pairs of cell lines carry alterations that are typical for this disease: loss of tumor suppressors (CDKN2A, CDKN2B), expression of fusion genes (ETV6-RUNX1, BCR-ABL1, MEF2D-BCL9) or of genes targeted by point mutations (KRAS A146T, NRAS G12C, PAX5 R38H). MEF2D-BCL9 and PAX R38H mutations in cell lines have hitherto been undescribed, suggesting that YCUB-4 (MEF2D-BCL9), PC-53 (PAX R38H) and their sister cell lines will be useful models to elucidate the function of these genes. All aberrations mentioned above occur in both sister cell lines, demonstrating that the sisters derive from a common ancestor. However, we also found mutations that are specific for one sister cell line only, pointing to individual subclones of the primary tumor as originating cells. Our data show that sequential sister cell lines can be used to study the clonal development of tumors and to elucidate the function of common and clone-specific mutations.
Highlights
For many decades, cell lines have enabled the modeling of human disease in cell culture for a better understanding of a plethora of pathophysiological processes and most importantly, for drug screening
In the domain of hematopoietic tumors, cell lines represent vital and powerful models in experimental systems to unravel the pro-leukemogenic roles of specific genetic mutations
The Whole Exome Sequencing (WES) data analysis indicated that the sister cell lines AT-1 and AT-2 consisted of subclones with KRAS A146T (Gca/Aca) or with NRAS G12C (Ggt/Tgt) mutations (Table 1)
Summary
Cell lines have enabled the modeling of human disease in cell culture for a better understanding of a plethora of pathophysiological processes and most importantly, for drug screening. Prior studies suggest that clonal mutations at relapse emerge from relapse-favoring subclones that already existed at diagnosis [4]. Their actual molecular and cellular input to therapy resistance and relapse remain, incompletely understood. The field of clonal evolution is an intensely discussed topic, both generally in cancer and in leukemia [5,6,7]. To obtain further insight into the relative impact of founding genomic alterations and acquired genetic alterations, we set out to examine the gene mutation status and gene expression of paired cell lines procured from ALL patients at diagnosis and at subsequent relapse or at other consecutive stages of their disease, aiming at a better understanding of the ALL relapse processes
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