MicroRNA-21 is Required for Hematopoietic Cell Viability After Radiation Exposure

Matthew V. Puccetti, Clare M. Adams, Tu Dan, Ajay Palagani, Brittany A. Simone, Tiziana DeAngelis, Christine M. Eischen, Nicole L. Simone

Research output: Contribution to journalArticle

Abstract

Purpose: Radiation therapy is an essential intervention used in the treatment of more than half of cancer patients. With the increasing use of hypofractionated radiation regimens, concurrent use of radiation and chemotherapy, targeted agents and immunotherapy, the risk of radiation-induced toxicities is increased. However, much remains unknown about the molecular underpinnings responsible for radiation-induced toxicity. MicroRNA (miRNA)are small, non-coding RNA involved in post-transcriptional regulation of gene expression. miR-21 is an oncomiR that is dysregulated in a significant fraction of human malignancies, and its overexpression is linked to poor overall survival, chemoresistance, and radioresistance in several human cancers. However, the contribution of miR-21 in governing radiation sensitivity in normal, untransformed cells, and the impact of silencing this miRNA in normal tissues remains largely unexplored. Materials and Methods: miR-21 levels were evaluated in tissues by qRT-PCR without and after total body irradiation (TBI). Mice lacking miR-21 were genetically engineered, subjected to TBI, and monitored for survival. Hematopoietic stem and progenitor cell (HSPC)numbers and function were assessed using flow cytometry, histology, complete blood cell counts, and bone marrow transplantation. Results: miR-21 expression was increased in radiosensitive tissues, but not in radioinsensitive tissues following TBI in wild-type mice, suggesting it may have a critical function in the normal tissue response to irradiation. Compared to wild-type mice, mice lacking one or both alleles of miR-21 showed reduced numbers of HSPCs and increased sensitivity to an LD50/30 dose of TBI with evidence of bone marrow failure. Transplantation of wild-type bone marrow into irradiated miR-21-deficient mice rescued the mice from death. Conclusions: Our data identify miR-21 as a critical component of HSPC viability and essential for bone marrow recovery following irradiation. Further investigation is warranted to determine whether miR-21 can be used to stratify patients at risk for hematopoietic toxicity following irradiation.

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radiation dosage
MicroRNAs
viability
Cell Survival
Whole-Body Irradiation
mice
Hematopoietic Stem Cells
bone marrow
irradiation
Radiation
toxicity
Blood Cell Count
radiation
transplantation
Bone Marrow Transplantation
Bone Marrow
blood cell count
cancer
Small Untranslated RNA
Neoplasms

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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MicroRNA-21 is Required for Hematopoietic Cell Viability After Radiation Exposure. / Puccetti, Matthew V.; Adams, Clare M.; Dan, Tu; Palagani, Ajay; Simone, Brittany A.; DeAngelis, Tiziana; Eischen, Christine M.; Simone, Nicole L.

In: International Journal of Radiation Oncology Biology Physics, 01.01.2019.

Research output: Contribution to journalArticle

Puccetti, Matthew V. ; Adams, Clare M. ; Dan, Tu ; Palagani, Ajay ; Simone, Brittany A. ; DeAngelis, Tiziana ; Eischen, Christine M. ; Simone, Nicole L. / MicroRNA-21 is Required for Hematopoietic Cell Viability After Radiation Exposure. In: International Journal of Radiation Oncology Biology Physics. 2019.
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abstract = "Purpose: Radiation therapy is an essential intervention used in the treatment of more than half of cancer patients. With the increasing use of hypofractionated radiation regimens, concurrent use of radiation and chemotherapy, targeted agents and immunotherapy, the risk of radiation-induced toxicities is increased. However, much remains unknown about the molecular underpinnings responsible for radiation-induced toxicity. MicroRNA (miRNA)are small, non-coding RNA involved in post-transcriptional regulation of gene expression. miR-21 is an oncomiR that is dysregulated in a significant fraction of human malignancies, and its overexpression is linked to poor overall survival, chemoresistance, and radioresistance in several human cancers. However, the contribution of miR-21 in governing radiation sensitivity in normal, untransformed cells, and the impact of silencing this miRNA in normal tissues remains largely unexplored. Materials and Methods: miR-21 levels were evaluated in tissues by qRT-PCR without and after total body irradiation (TBI). Mice lacking miR-21 were genetically engineered, subjected to TBI, and monitored for survival. Hematopoietic stem and progenitor cell (HSPC)numbers and function were assessed using flow cytometry, histology, complete blood cell counts, and bone marrow transplantation. Results: miR-21 expression was increased in radiosensitive tissues, but not in radioinsensitive tissues following TBI in wild-type mice, suggesting it may have a critical function in the normal tissue response to irradiation. Compared to wild-type mice, mice lacking one or both alleles of miR-21 showed reduced numbers of HSPCs and increased sensitivity to an LD50/30 dose of TBI with evidence of bone marrow failure. Transplantation of wild-type bone marrow into irradiated miR-21-deficient mice rescued the mice from death. Conclusions: Our data identify miR-21 as a critical component of HSPC viability and essential for bone marrow recovery following irradiation. Further investigation is warranted to determine whether miR-21 can be used to stratify patients at risk for hematopoietic toxicity following irradiation.",
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AU - Puccetti, Matthew V.

AU - Adams, Clare M.

AU - Dan, Tu

AU - Palagani, Ajay

AU - Simone, Brittany A.

AU - DeAngelis, Tiziana

AU - Eischen, Christine M.

AU - Simone, Nicole L.

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