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Autologous hematopoietic stem cell transplant induces the molecular aging of T-cells in multiple myeloma

Bone Marrow Transplantation volume 50, pages 1379–1381 (2015)Cite this article

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Multiple myeloma (MM) is an incurable hematologic malignancy diagnosed primarily in older adults. As the population ages, myeloma incidence is expected to increase at a higher rate than many other malignancies.1 Approved chemotherapy and targeted regimens for older adults with MM are numerous and exhibit distinct toxicities. The physiological heterogeneity of older adults makes it challenging for physicians to identify the most effective, yet best tolerated regimen, for each MM patient. As such, use of a two-drug regimen, three-drug regimen, or intensive autologous hematopoietic stem cell transplant (AHSCT) is often subjective. Consequently, AHSCT eligibility is subjectively applied and more objective measures are warranted to better understand health status in older adults. We believe that objective markers of physiological age will improve treatment stratification and will be an additional tool in understanding how treatment and transplant have an impact on health status.

The molecular biomarker, p16INK4a (p16) is an established marker of systemic cellular senescence associated with physiological aging. p16 expression increases ~16-fold over an individual’s lifetime and can be readily measured in peripheral blood T-lymphocytes (PBTLs).2 p16 originates from the INK4/ARF locus on human chromosome 9p21 and belongs to the INK4 family of cyclin-dependent kinase inhibitors (CDKis). These CDKis prevent cell cycle progression into S-phase by blocking phosphorylation of the retinoblastoma tumor suppressor by CDK4/6.3 On a cellular level, p16 expression increases with stress (for example, DNA-damaging stimuli, telomere erosion and oncogene expression) and, with prolonged induction, can promote an irreversible cell cycle arrest termed ‘cellular senescence.’ In humans, p16 rises exponentially with chronologic age and this rate of increase is further accelerated by physical inactivity, tobacco use, chronic HIV infection and cytotoxic chemotherapy.2, 4 The regulation of p16 expression is also linked to age-related conditions (that is, cardiovascular disease, diabetes and decreased physical function) through single-nucleotide polymorphisms located near the INK4/ARF locus.5, 6, 7 To date, p16 expression has not been examined as a surrogate for biologic age in MM, a disease where treatment stratification is often based on chronologic age.

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Acknowledgements

This study was supported by D Warren Brown Foundation and OSUCCC Comprehensive CCC grant P30 CA016058-39.

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Authors and Affiliations

  1. Division of Hematology, Ohio State University, Columbus, OH, USA

    A Rosko, C Hofmeister, D Benson, Y Efebera, Y Huang & J C Byrd

  2. Department of Molecular Genetics, Ohio State University, Columbus, OH, USA

    J Gillahan & C E Burd

  3. Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH, USA

    J Gillahan & C E Burd

  4. Division of Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH, USA

    J C Byrd

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  1. A Rosko
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Correspondence to A Rosko.

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Supplementary Information accompanies this paper on Bone Marrow Transplantation website

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Rosko, A., Hofmeister, C., Benson, D. et al. Autologous hematopoietic stem cell transplant induces the molecular aging of T-cells in multiple myeloma. Bone Marrow Transplant 50, 1379–1381 (2015). https://doi.org/10.1038/bmt.2015.143

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