title: Chemotherapy and Stem Cell Transplantation Increase p16INK4aExpression, a Biomarker of T-cell Aging.
abstract: 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 p16INK4aexpression 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 p16INK4aexpression 6months following transplantation. Patients receiving autologous transplant experienced a larger increase in p16INK4aexpression (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.
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: William A
authors: WA
authors: Wood
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Janakiraman
authors: J
authors: Krishnamurthy
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Natalia
authors: N
authors: Mitin
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Chad
authors: C
authors: Torrice
authors: Department of Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Joel S
authors: JS
authors: Parker
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Anna C
authors: AC
authors: Snavely
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Thomas C
authors: TC
authors: Shea
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: Jonathan S
authors: JS
authors: Serody
authors: Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA. Electronic address: NES@med.unc.edu.
authors: Norman E
authors: NE
authors: Sharpless
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D016000:Cluster Analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D033581:Stem Cell Transplantation / Q000379:methods; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: Aging; Exhaustion; Senescence