Resistance to DNA damage–induced apoptosis is a hallmark of cancer and a major cause of treatment failure and lethal disease outcome. A tumor entity that is largely resistant to DNA-damaging therapies including chemo- or radiotherapy is renal cell carcinoma (RCC). This study was designed to explore the underlying molecular mechanisms of DNA damage resistance in RCC to develop strategies to resensitize tumor cells to DNA damage–induced apoptosis. Here, we show that apoptosis-resistant RCC cells have a disconnect between activation of p53 and upregulation of the downstream proapoptotic protein p53 upregulated modulator of apoptosis (PUMA). We demonstrate that this disconnect is not caused by gene-specific repression through CCCTC-binding factor (CTCF) but instead by aberrant chromatin compaction. Treatment with an HDAC inhibitor was found to effectively reactivate PUMA expression on the mRNA and protein level and to revert resistance to DNA damage–induced cell death. Ectopic expression of PUMA was found to resensitize a panel of RCC cell lines to four different DNA-damaging agents tested. Remarkably, all RCC cell lines analyzed were wild-type for p53, and a knockdown was likewise able to sensitize RCC cells to acute genotoxic stress. Taken together, our results indicate that DNA damage resistance in RCC is reversible, involves the p53-PUMA axis, and is potentially targetable to improve the oncological outcomes of RCC patients.

Sorafenib in standard dosage, given preoperatively for 28 days, was clinically active in downsizing tumors in patients with locally confined, non-metastatic RCC together but led to an enhanced functional ITH in the residual tumor tissue.

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Background Leukemic stem cells (LSCs) of chronic myeloid leukemia (CML), persisting in the bone marrow (BM) niche, could be responsible for the relapses within the patients of whom the treatment‐free remission (TFR) had been attempted. We assessed the presence of the CML LSCs in the peripheral blood (PB) and concurrently in the BM in the patients with chronic‐phase CML (CP CML). Patients and Methods Thirty‐eight patients with CP CML were included into the study. CD45+/CD34+/CD38− cells with positive CD26 expression were considered as CML LSCs (CD26+ LSC) by using multiparameter flow cytometry (FCM). Results Mean BCR‐ABL, PB LSC, and BM LSC were 58.528 IS (37.405‐83.414 IS), 237.5 LSC/μL (16‐737.5 LSC/μL), and 805 LSC/106 WBCs (134.6‐2470 LSC/106 WBCs), respectively, in newly diagnosed CML patients. In the patients with BCR‐ABL positive hematopoiesis, mean BCR‐ABL, PB LSCs, and BM LSCs were 30.09 IS (0.024‐147.690 IS), 13.5 LSC/μL (0‐248.7 LSC/μL) and 143.5 LSC/106 WBCs (9‐455.2 LSC/106 WBCs), respectively. No CML LSCs were detected in PB of patients who achieved deep molecular response (DMR). BM LSCs of the patients who were in DMR were 281.1 LSC/106 WBCs (3.1‐613.7 LSC/106 WBCs). The amount of PB LSCs was highest in patients with newly diagnosed CML (P < .001). Conclusion LSCs persisted in the BM of the patients with DMR, whereas there was no LSCs in the peripheral blood. The investigation of the CML LSCs in bone marrow before deciding TKI discontinuation could be justified to achieve and maintain stable TFR.