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p21(WAF1) is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21(WAF1) in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21(WAF1) was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21(WAF1) in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21(WAF1) silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21(WAF1) expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21(WAF1) regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat.

Over the past two decades, it has become increasingly apparent that telomerase-mediated telomere maintenance plays a crucial role in hematopoiesis. Supporting evidence is underscored by recent findings of mutations in genes involved in telomerase-mediated telomere maintenance that contribute to the pathogenesis of bone marrow failure syndromes. More recently described telomere-independent functions of telomerase are also likely to contribute to both normal hematopoiesis and hematologic diseases. The high levels of telomerase detected in aggressive leukemias have fueled fervent investigation into diverse approaches to targeting telomerase in hematologic malignancies. Successful preclinical investigations that employed genetic strategies, oligonucleotides, small-molecule inhibitors and immunotherapy have resulted in a rapid translation to clinical trials. Further investigation of telomere-independent functions of telomerase and detailed preclinical studies of telomerase inhibition in both normal and malignant hematopoiesis will be invaluable for refining treatments to effectively and safely exploit telomerase as a therapeutic target in hematologic malignancies.