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Title: Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers [Ionizing radiation as a modulator of bone marrow cell reprogramming: low doses as a driver for associated hematological cancers]

Abstract

Exposure of individuals to ionizing radiation (IR), as in the case of astronauts exploring space or radiotherapy cancer patients, increases their risk of developing secondary cancers and other health-related problems. Bone marrow (BM), the site in the body where hematopoietic stem cell (HSC) self-renewal and differentiation to mature blood cells occurs, is extremely sensitive to low-dose IR, including irradiation by high-charge and high-energy particles. Low-dose IR induces DNA damage and persistent oxidative stress in the BM hematopoietic cells. Inefficient DNA repair processes in HSC and early hematopoietic progenitors can lead to an accumulation of mutations whereas long-lasting oxidative stress can impair hematopoiesis itself, thereby causing long-term damage to hematopoietic cells in the BM niche. We report here that low-dose 1H- and 56Fe-IR significantly decreased the hematopoietic early and late multipotent progenitor (E- and L-MPP, respectively) cell numbers in mouse BM over a period of up to 10 months after exposure. Both 1H- and 56Fe-IR increased the expression of pluripotent stem cell markers Sox2, Nanog, and Oct4 in L-MPPs and 10 months post-IR exposure. We postulate that low doses of 1H- and 56Fe-IR may induce endogenous cellular reprogramming of BM hematopoietic progenitor cells to assume a more primitive pluripotent phenotype andmore » that IR-induced oxidative DNA damage may lead to mutations in these BM progenitors. This could then be propagated to successive cell lineages. Persistent impairment of BM progenitor cell populations can disrupt hematopoietic homeostasis and lead to hematologic disorders, and these findings warrant further mechanistic studies into the effects of low-dose IR on the functional capacity of BM-derived hematopoietic cells including their self-renewal and pluripotency.« less

Authors:
 [1];  [2];  [1];  [3];  [4];  [5];  [1];  [6];  [7]
  1. Boston University School of Medicine, Boston, MA (United States). Whitaker Cardiovascular Institute
  2. GeneSys Research Institute, Boston, MA (United States). Cardiovascular Research Center
  3. Yale School of Medicine, New Haven, CT (United States). Yale Cardiovascular Research Center
  4. Wake Forest School of Medicine, Winston-Salem, NC (United States). Wake Forest Institute for Regenerative Medicine
  5. University of California Davis, Sacramento, CA (United States). Radiation Oncology, School of Medicine; Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  6. GeneSys Research Institute, Boston, MA (United States). Cardiovascular Research Center ; Tufts University School of Medicine, Boston, MA (United States)
  7. Boston University School of Medicine, Boston, MA (United States). Whitaker Cardiovascular Institute; GeneSys Research Institute, Boston, MA (United States). Cardiovascular Research Center; Tufts University School of Medicine, Boston, MA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1466139
Report Number(s):
LLNL-JRNL-737728
Journal ID: ISSN 2234-943X; 890200
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Frontiers in Oncology
Additional Journal Information:
Journal Volume: 5; Journal Issue: no. 231; Journal ID: ISSN 2234-943X
Publisher:
Frontiers Research Foundation
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE

Citation Formats

Muralidharan, Sujatha, Sasi, Sharath P., Zuriaga, Maria A., Hirschi, Karen K., Porada, Christopher D., Coleman, Matthew A., Walsh, Kenneth X., Yan, Xinhua, and Goukassian, David A. Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers [Ionizing radiation as a modulator of bone marrow cell reprogramming: low doses as a driver for associated hematological cancers]. United States: N. p., 2015. Web. doi:10.3389/fonc.2015.00231.
Muralidharan, Sujatha, Sasi, Sharath P., Zuriaga, Maria A., Hirschi, Karen K., Porada, Christopher D., Coleman, Matthew A., Walsh, Kenneth X., Yan, Xinhua, & Goukassian, David A. Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers [Ionizing radiation as a modulator of bone marrow cell reprogramming: low doses as a driver for associated hematological cancers]. United States. doi:10.3389/fonc.2015.00231.
Muralidharan, Sujatha, Sasi, Sharath P., Zuriaga, Maria A., Hirschi, Karen K., Porada, Christopher D., Coleman, Matthew A., Walsh, Kenneth X., Yan, Xinhua, and Goukassian, David A. Wed . "Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers [Ionizing radiation as a modulator of bone marrow cell reprogramming: low doses as a driver for associated hematological cancers]". United States. doi:10.3389/fonc.2015.00231. https://www.osti.gov/servlets/purl/1466139.
@article{osti_1466139,
title = {Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers [Ionizing radiation as a modulator of bone marrow cell reprogramming: low doses as a driver for associated hematological cancers]},
author = {Muralidharan, Sujatha and Sasi, Sharath P. and Zuriaga, Maria A. and Hirschi, Karen K. and Porada, Christopher D. and Coleman, Matthew A. and Walsh, Kenneth X. and Yan, Xinhua and Goukassian, David A.},
abstractNote = {Exposure of individuals to ionizing radiation (IR), as in the case of astronauts exploring space or radiotherapy cancer patients, increases their risk of developing secondary cancers and other health-related problems. Bone marrow (BM), the site in the body where hematopoietic stem cell (HSC) self-renewal and differentiation to mature blood cells occurs, is extremely sensitive to low-dose IR, including irradiation by high-charge and high-energy particles. Low-dose IR induces DNA damage and persistent oxidative stress in the BM hematopoietic cells. Inefficient DNA repair processes in HSC and early hematopoietic progenitors can lead to an accumulation of mutations whereas long-lasting oxidative stress can impair hematopoiesis itself, thereby causing long-term damage to hematopoietic cells in the BM niche. We report here that low-dose 1H- and 56Fe-IR significantly decreased the hematopoietic early and late multipotent progenitor (E- and L-MPP, respectively) cell numbers in mouse BM over a period of up to 10 months after exposure. Both 1H- and 56Fe-IR increased the expression of pluripotent stem cell markers Sox2, Nanog, and Oct4 in L-MPPs and 10 months post-IR exposure. We postulate that low doses of 1H- and 56Fe-IR may induce endogenous cellular reprogramming of BM hematopoietic progenitor cells to assume a more primitive pluripotent phenotype and that IR-induced oxidative DNA damage may lead to mutations in these BM progenitors. This could then be propagated to successive cell lineages. Persistent impairment of BM progenitor cell populations can disrupt hematopoietic homeostasis and lead to hematologic disorders, and these findings warrant further mechanistic studies into the effects of low-dose IR on the functional capacity of BM-derived hematopoietic cells including their self-renewal and pluripotency.},
doi = {10.3389/fonc.2015.00231},
journal = {Frontiers in Oncology},
number = no. 231,
volume = 5,
place = {United States},
year = {2015},
month = {10}
}

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