Constitutive Expression of Inducible Cyclic Adenosine Monophosphate Early Repressor (ICER) in Cycling Quiescent Hematopoietic Cells

Implications for Aging Hematopoietic Stem Cells

Steven J. Greco, Ghassan Yehia, Julius A. Potian, Carlos Molina, Pranela Rameshwar

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Despite extensive insights on the interaction between hematopoietic stem cells (HSCs) and the supporting bone marrow (BM) stroma in hematopoietic homeostasis there remains unanswered questions on HSC regulation. We report on the mechanism by which HSCs attain cycling quiescence by addressing a role for inducible cyclic AMP early repressor (ICER). ICER negatively transcriptional regulators of cAMP activators such as CREM and CREB. These activators can be induced by hematopoietic stimulators such as cytokines. We isolated subsets of hematopoietic cells from ten healthy donors: CD34+CD38/c-kit+ (primitive progenitor), CD34+CD38+/c-kitlow (mature progenitor) and CD34CD38+/−/c-kitlow/− (differentiated lineage-). The relative maturity of the progenitors were verified in long-term culture initiating assay. Immunoprecipitation indicated the highest level of ICER in the nuclear extracts of CD34+/CD38 cells. Phospho (p)-CREM was also present suggesting a balance between ICER and p-CREM in HSC. ICER seems to be responsible for decrease in G1 transition, based on reduced Cdk4 protein, decreased proliferation and functional studies with propidium iodide. There were no marked changes in the cycling inhibitors, p15 and p-Rb, suggesting that ICER may act independently of other cycling inhibitors. The major effects of ICER were validated with BM mononuclear cells (BMNCs) in which ICER was ectopically expressed, and with BMNCs resistant to 5-fluorouracil- or cyclophosphamide. In total, this study ascribes a novel role for ICER in G1 checkpoint regulation in HSCs. These findings are relevant to gene therapy that require engineering of HSCs, age-related disorders that are associated with hematopoietic dysfunction and other hematological disorders.

Original languageEnglish
Pages (from-to)116-126
Number of pages11
JournalStem Cell Reviews and Reports
Volume13
Issue number1
DOIs
StatePublished - 1 Feb 2017

Fingerprint

Cell Aging
Hematopoietic Stem Cells
Cyclic AMP
Cyclin-Dependent Kinase 4
Propidium
Immunoprecipitation
Fluorouracil
Bone Marrow Cells
Genetic Therapy
Cyclophosphamide
Homeostasis
Bone Marrow
Cytokines

Keywords

  • Bone marrow
  • Cell cycle
  • Cytokines
  • Hematopoietic stem cell
  • Inducible cAMP early repressor
  • Transcription factors

Cite this

@article{2e7542d1498146ae88fd999cc104800a,
title = "Constitutive Expression of Inducible Cyclic Adenosine Monophosphate Early Repressor (ICER) in Cycling Quiescent Hematopoietic Cells: Implications for Aging Hematopoietic Stem Cells",
abstract = "Despite extensive insights on the interaction between hematopoietic stem cells (HSCs) and the supporting bone marrow (BM) stroma in hematopoietic homeostasis there remains unanswered questions on HSC regulation. We report on the mechanism by which HSCs attain cycling quiescence by addressing a role for inducible cyclic AMP early repressor (ICER). ICER negatively transcriptional regulators of cAMP activators such as CREM and CREB. These activators can be induced by hematopoietic stimulators such as cytokines. We isolated subsets of hematopoietic cells from ten healthy donors: CD34+CD38−/c-kit+ (primitive progenitor), CD34+CD38+/c-kitlow (mature progenitor) and CD34−CD38+/−/c-kitlow/− (differentiated lineage-). The relative maturity of the progenitors were verified in long-term culture initiating assay. Immunoprecipitation indicated the highest level of ICER in the nuclear extracts of CD34+/CD38− cells. Phospho (p)-CREM was also present suggesting a balance between ICER and p-CREM in HSC. ICER seems to be responsible for decrease in G1 transition, based on reduced Cdk4 protein, decreased proliferation and functional studies with propidium iodide. There were no marked changes in the cycling inhibitors, p15 and p-Rb, suggesting that ICER may act independently of other cycling inhibitors. The major effects of ICER were validated with BM mononuclear cells (BMNCs) in which ICER was ectopically expressed, and with BMNCs resistant to 5-fluorouracil- or cyclophosphamide. In total, this study ascribes a novel role for ICER in G1 checkpoint regulation in HSCs. These findings are relevant to gene therapy that require engineering of HSCs, age-related disorders that are associated with hematopoietic dysfunction and other hematological disorders.",
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author = "Greco, {Steven J.} and Ghassan Yehia and Potian, {Julius A.} and Carlos Molina and Pranela Rameshwar",
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Constitutive Expression of Inducible Cyclic Adenosine Monophosphate Early Repressor (ICER) in Cycling Quiescent Hematopoietic Cells : Implications for Aging Hematopoietic Stem Cells. / Greco, Steven J.; Yehia, Ghassan; Potian, Julius A.; Molina, Carlos; Rameshwar, Pranela.

In: Stem Cell Reviews and Reports, Vol. 13, No. 1, 01.02.2017, p. 116-126.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Constitutive Expression of Inducible Cyclic Adenosine Monophosphate Early Repressor (ICER) in Cycling Quiescent Hematopoietic Cells

T2 - Implications for Aging Hematopoietic Stem Cells

AU - Greco, Steven J.

AU - Yehia, Ghassan

AU - Potian, Julius A.

AU - Molina, Carlos

AU - Rameshwar, Pranela

PY - 2017/2/1

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N2 - Despite extensive insights on the interaction between hematopoietic stem cells (HSCs) and the supporting bone marrow (BM) stroma in hematopoietic homeostasis there remains unanswered questions on HSC regulation. We report on the mechanism by which HSCs attain cycling quiescence by addressing a role for inducible cyclic AMP early repressor (ICER). ICER negatively transcriptional regulators of cAMP activators such as CREM and CREB. These activators can be induced by hematopoietic stimulators such as cytokines. We isolated subsets of hematopoietic cells from ten healthy donors: CD34+CD38−/c-kit+ (primitive progenitor), CD34+CD38+/c-kitlow (mature progenitor) and CD34−CD38+/−/c-kitlow/− (differentiated lineage-). The relative maturity of the progenitors were verified in long-term culture initiating assay. Immunoprecipitation indicated the highest level of ICER in the nuclear extracts of CD34+/CD38− cells. Phospho (p)-CREM was also present suggesting a balance between ICER and p-CREM in HSC. ICER seems to be responsible for decrease in G1 transition, based on reduced Cdk4 protein, decreased proliferation and functional studies with propidium iodide. There were no marked changes in the cycling inhibitors, p15 and p-Rb, suggesting that ICER may act independently of other cycling inhibitors. The major effects of ICER were validated with BM mononuclear cells (BMNCs) in which ICER was ectopically expressed, and with BMNCs resistant to 5-fluorouracil- or cyclophosphamide. In total, this study ascribes a novel role for ICER in G1 checkpoint regulation in HSCs. These findings are relevant to gene therapy that require engineering of HSCs, age-related disorders that are associated with hematopoietic dysfunction and other hematological disorders.

AB - Despite extensive insights on the interaction between hematopoietic stem cells (HSCs) and the supporting bone marrow (BM) stroma in hematopoietic homeostasis there remains unanswered questions on HSC regulation. We report on the mechanism by which HSCs attain cycling quiescence by addressing a role for inducible cyclic AMP early repressor (ICER). ICER negatively transcriptional regulators of cAMP activators such as CREM and CREB. These activators can be induced by hematopoietic stimulators such as cytokines. We isolated subsets of hematopoietic cells from ten healthy donors: CD34+CD38−/c-kit+ (primitive progenitor), CD34+CD38+/c-kitlow (mature progenitor) and CD34−CD38+/−/c-kitlow/− (differentiated lineage-). The relative maturity of the progenitors were verified in long-term culture initiating assay. Immunoprecipitation indicated the highest level of ICER in the nuclear extracts of CD34+/CD38− cells. Phospho (p)-CREM was also present suggesting a balance between ICER and p-CREM in HSC. ICER seems to be responsible for decrease in G1 transition, based on reduced Cdk4 protein, decreased proliferation and functional studies with propidium iodide. There were no marked changes in the cycling inhibitors, p15 and p-Rb, suggesting that ICER may act independently of other cycling inhibitors. The major effects of ICER were validated with BM mononuclear cells (BMNCs) in which ICER was ectopically expressed, and with BMNCs resistant to 5-fluorouracil- or cyclophosphamide. In total, this study ascribes a novel role for ICER in G1 checkpoint regulation in HSCs. These findings are relevant to gene therapy that require engineering of HSCs, age-related disorders that are associated with hematopoietic dysfunction and other hematological disorders.

KW - Bone marrow

KW - Cell cycle

KW - Cytokines

KW - Hematopoietic stem cell

KW - Inducible cAMP early repressor

KW - Transcription factors

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DO - 10.1007/s12015-016-9701-5

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SN - 1550-8943

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