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bioRxiv · 10.64898/2026.02.12.705420

Upregulation of Genetic Markers of Poor Prognosis following Chemotherapy in Acute Myeloid Leukemia Cells

Taylor, A.·Strasser, M. K.·Ng, M.·Rubin, I.·Kaipainen, A.·Pisco, A. O.·Huang, S.
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Abstract

Chemoresistance, a leading cause of treatment failure in cancer, is commonly explained by Darwinian selection of treatment-resistant cell clones. However, recurring resistant tumors invariably display complex phenotypes that contribute to increased malignancy, unlikely to have been selected for by chemotherapy. The growing awareness of (non - genetic) phenotypic plasticity led to the hypothesis that chemotherapy, while reducing tumor burden, also inflicts cell stress that induces stem-like states in cells that survive treatment. Here we examined the transcriptomes of HL-60 leukemic cancer cells that survived exposure to three commonly used drugs at submaximal doses for two to four days, and compared differentially expressed genes to those associated with prognosis in public transcriptome databases of acute myeloid leukemia cohorts. While among the genes differentially upregulated in surviving cells, some reflect the therapeutic effect of chemotherapy as they were associated with favorable outcomes in cohort data, many genes upregulated were associated with poor survival, notably genes involved in stemness, epithelial-mesenchymal transition (EMT), inflammation, drug resistance, and apoptosis evasion. These findings support the idea that treatment effectiveness is the net result of an intrinsic tradeoff: Cytocidal treatment, intended to quantitatively reduce cancer cells, also qualitatively increases the malignancy of non-killed cells, which could contribute to residual disease and relapse. This result has implications for drug screening of new therapeutics, as well as in vitro profiling of patient-derived tumor cell susceptibility to existing drugs, which only assess suppression of cancer cell growth and survival. Statement of SignificanceCells surviving chemotherapy upregulate many genes that may affect prognosis. Therefore, drug screening must embrace a more holistic assessment of the biological quality of cell response beyond the rate of cell killing.

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Taylor, A., Strasser, M. K., Ng, M., Rubin, I., Kaipainen, A., Pisco, A. O., Huang, S.. 2026-02-15. Upregulation of Genetic Markers of Poor Prognosis following Chemotherapy in Acute Myeloid Leukemia Cells. https://doi.org/10.64898/2026.02.12.705420

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