Chemotherapy and Stem Cell Transplantation Increase p16INK4a Expression, a Biomarker of T-cell Aging

• Published in: EBioMedicine Vol. 11; no. C; pp. 227 - 238
• Main Authors: Wood, William A., Krishnamurthy, Janakiraman, Mitin, Natalia, Torrice, Chad, Parker, Joel S., Snavely, Anna C., Shea, Thomas C., Serody, Jonathan S., Sharpless, Norman E.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2016; Elsevier
• Subjects: Aging; Exhaustion; Research Paper; Senescence; Aging; Senescence; Exhaustion
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.08.029

The expression of markers of cellular senescence increases exponentially in multiple tissues with aging. Age-related physiological changes may contribute to adverse outcomes in cancer survivors. To investigate the impact of high dose chemotherapy and stem cell transplantation on senescence markers in vivo, we collected blood and clinical data from a cohort of 63 patients undergoing hematopoietic cell transplantation. The expression of p16INK4a, a well-established senescence marker, was determined in T-cells before and 6months after transplant. RNA sequencing was performed on paired samples from 8 patients pre- and post-cancer therapy. In patients undergoing allogeneic transplant, higher pre-transplant p16INK4a expression was associated with a greater number of prior cycles of chemotherapy received (p=0.003), prior autologous transplantation (p=0.01) and prior exposure to alkylating agents (p=0.01). Transplantation was associated with a marked increase in p16INK4a expression 6months following transplantation. Patients receiving autologous transplant experienced a larger increase in p16INK4a expression (3.1-fold increase, p=0.002) than allogeneic transplant recipients (1.9-fold increase, p=0.0004). RNA sequencing of T-cells pre- and post- autologous transplant or cytotoxic chemotherapy demonstrated increased expression of transcripts associated with cellular senescence and physiological aging. Cytotoxic chemotherapy, especially alkylating agents, and stem cell transplantation strongly accelerate expression of a biomarker of molecular aging in T-cells. •Peripheral blood T-cell senescence, as measured by the marker p16INK4a, increases following autologous or allogeneic HSCT.•RNAseq of T-cells post- auto HSCT or chemotherapy show increased expression of transcripts associated with senescence.•Autologous HCT in particular induces a stronger effect on Tcell p16INK4a expression than any other environmental stimulus tested to date. Human chronological aging is associated with increased expression of markers of cellular aging (senescence). Cancer chemotherapy can produce frailty syndromes – recipients of cancer treatment may experience physiological changes ordinarily seen in individuals of more advanced chronological age. In our study, we found that a well-known marker of cellular senescence, p16INK4a, increased in patients following autologous or allogeneic hematopoietic cell transplantation. Expression of p16INK4a was higher in patients exposed to greater amounts of chemotherapy before transplant and those exposed to specific types of chemotherapy. These findings may ultimately influence clinical decision-making for patients with diseases that are commonly treated with transplantation.