Molecular Mechanism of Transforming Growth Factor Beta-mediated Cell-cycle Modulation in Primary Human CD34(+) Progenitors

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2002 Jan 10

PMID 11781230

Citations 13

Authors

Mo A Dao

Joseph Hwa

Jan A Nolta

Affiliations

Soon will be listed here.

Abstract

The mechanisms by which transforming growth factor beta (TGF-beta) exerts a negative effect on cell-cycle entry in primary human hematopoietic stem/progenitor cells were examined at the molecular and cellular levels. After treatment of primary human CD34+ progenitors with TGF-beta there was a decrease in the levels of cyclin D2 protein and an increase in levels of the cyclin-dependent kinase inhibitor (CDKI) p15 as compared to the levels in untreated cells. The converse was true after addition of neutralizing anti-TGF-beta antibody. Administration of TGF-beta to CD34+ cells in the presence of cytokines prevented retinoblastoma protein (pRb) phosphorylation, which occurred in the same cells treated with cytokines alone or cytokines and anti-TGF-beta antibody. Neutralization of TGF-beta during 24 to 48 hours of culture with cytokines significantly increased the number of colony-forming progenitors, but did not modulate the human stem cell pool, as measured in 6- to 12-month xenotransplantation assays. Equivalent numbers of human B, T, and myeloid cells were obtained after transplantation of cells treated with or without neutralization of TGF-beta.

Citing Articles

Loss of SMAD1 in acute myeloid leukemia with and fusion genes.

Dietsche L, Stirm K, Lysenko V, Schneidawind C, Tzankov A, Muller A Front Oncol. 2025; 14:1481713.

PMID: 39834944 PMC: 11743462. DOI: 10.3389/fonc.2024.1481713.

Role of innate immunological/inflammatory pathways in myelodysplastic syndromes and AML: a narrative review.

Vegivinti C, Keesari P, Veeraballi S, Martins Maia C, Mehta A, Lavu R Exp Hematol Oncol. 2023; 12(1):60.

PMID: 37422676 PMC: 10329313. DOI: 10.1186/s40164-023-00422-1.

Isolation, Maintenance and Expansion of Adult Hematopoietic Stem/Progenitor Cells and Leukemic Stem Cells.

Mayer I, Hoelbl-Kovacic A, Sexl V, Doma E Cancers (Basel). 2022; 14(7).

PMID: 35406494 PMC: 8996967. DOI: 10.3390/cancers14071723.

Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34 Hematopoietic Progenitor Cells.

Hancock M, Crawford L, Pham A, Mitchell J, Struthers H, Yurochko A Cell Host Microbe. 2019; 27(1):104-114.e4.

PMID: 31866424 PMC: 6952548. DOI: 10.1016/j.chom.2019.11.013.

Rapamycin enhances the antiproliferative effect of transforming growth factor-β on MCF-7 human breast cancer cells.

Wang G, Yin T Exp Ther Med. 2017; 14(1):748-752.

PMID: 28672994 PMC: 5488720. DOI: 10.3892/etm.2017.4557.

References

Hao Q, Thiemann F, Petersen D, Smogorzewska E, Crooks G . Extended long-term culture reveals a highly quiescent and primitive human hematopoietic progenitor population. Blood. 1996; 88(9):3306-13. View

Dao M, Taylor N, Nolta J . Reduction in levels of the cyclin-dependent kinase inhibitor p27(kip-1) coupled with transforming growth factor beta neutralization induces cell-cycle entry and increases retroviral transduction of primitive human hematopoietic cells. Proc Natl Acad Sci U S A. 1998; 95(22):13006-11. PMC: 23687. DOI: 10.1073/pnas.95.22.13006. View

Eaves C, Cashman J, Kay R, Dougherty G, Otsuka T, Gaboury L . Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. II. Analysis of positive and negative regulators produced by stromal cells within the adherent layer. Blood. 1991; 78(1):110-7. View

Bodine D, Karlsson S, Nienhuis A . Combination of interleukins 3 and 6 preserves stem cell function in culture and enhances retrovirus-mediated gene transfer into hematopoietic stem cells. Proc Natl Acad Sci U S A. 1989; 86(22):8897-901. PMC: 298397. DOI: 10.1073/pnas.86.22.8897. View

Polyak K, Kato J, Solomon M, Sherr C, Massague J, Roberts J . p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994; 8(1):9-22. DOI: 10.1101/gad.8.1.9. View

Glimm H, Eisterer W, Lee K, Cashman J, Holyoake T, Nicolini F . Previously undetected human hematopoietic cell populations with short-term repopulating activity selectively engraft NOD/SCID-beta2 microglobulin-null mice. J Clin Invest. 2001; 107(2):199-206. PMC: 199177. DOI: 10.1172/JCI11519. View

Fortunel N, Hatzfeld J, Kisselev S, Monier M, Ducos K, Cardoso A . Release from quiescence of primitive human hematopoietic stem/progenitor cells by blocking their cell-surface TGF-beta type II receptor in a short-term in vitro assay. Stem Cells. 2000; 18(2):102-11. DOI: 10.1634/stemcells.18-2-102. View

Driscoll B, Tang A, Hu Y, Yan C, Fu Y, Luo Y . Discovery of a regulatory motif that controls the exposure of specific upstream cyclin-dependent kinase sites that determine both conformation and growth suppressing activity of pRb. J Biol Chem. 1999; 274(14):9463-71. DOI: 10.1074/jbc.274.14.9463. View

Sutton R, Reitsma M, Uchida N, Brown P . Transduction of human progenitor hematopoietic stem cells by human immunodeficiency virus type 1-based vectors is cell cycle dependent. J Virol. 1999; 73(5):3649-60. PMC: 104140. DOI: 10.1128/JVI.73.5.3649-3660.1999. View

10.

Lomo J, Blomhoff H, Beiske K, Stokke T, Smeland E . TGF-beta 1 and cyclic AMP promote apoptosis in resting human B lymphocytes. J Immunol. 1995; 154(4):1634-43. View

11.

Dao M, Hashino K, Kato I, Nolta J . Adhesion to fibronectin maintains regenerative capacity during ex vivo culture and transduction of human hematopoietic stem and progenitor cells. Blood. 1998; 92(12):4612-21. View

12.

Gothot A, Pyatt R, McMahel J, Rice S, Srour E . Functional heterogeneity of human CD34(+) cells isolated in subcompartments of the G0 /G1 phase of the cell cycle. Blood. 1997; 90(11):4384-93. View

13.

Della Ragione F, Borriello A, Mastropietro S, DELLA PIETRA V, Monno F, Gabutti V . Expression of G1-phase cell cycle genes during hematopoietic lineage. Biochem Biophys Res Commun. 1997; 231(1):73-6. DOI: 10.1006/bbrc.1997.5938. View

14.

Matsushime H, Quelle D, Shurtleff S, Shibuya M, Sherr C, Kato J . D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol. 1994; 14(3):2066-76. PMC: 358567. DOI: 10.1128/mcb.14.3.2066-2076.1994. View

15.

Dao M, Nolta J . Molecular control of cell cycle progression in primary human hematopoietic stem cells: methods to increase levels of retroviral-mediated transduction. Leukemia. 1999; 13(10):1473-80. DOI: 10.1038/sj.leu.2401537. View

16.

Nolta J, Dao M, Wells S, Smogorzewska E, Kohn D . Transduction of pluripotent human hematopoietic stem cells demonstrated by clonal analysis after engraftment in immune-deficient mice. Proc Natl Acad Sci U S A. 1996; 93(6):2414-9. PMC: 39811. DOI: 10.1073/pnas.93.6.2414. View

17.

Cashman J, Eaves A, Raines E, Ross R, Eaves C . Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. I. Stimulatory role of a variety of mesenchymal cell activators and inhibitory role of TGF-beta. Blood. 1990; 75(1):96-101. View

18.

Yu J, Soma T, Hanazono Y, Dunbar C . Abrogation of TGF-beta activity during retroviral transduction improves murine hematopoietic progenitor and repopulating cell gene transfer efficiency. Gene Ther. 1999; 5(9):1265-71. DOI: 10.1038/sj.gt.3300732. View

19.

Lardon F, Snoeck H, Nijs G, Lenjou M, PEETERMANS M, Rodrigus I . Transforming growth factor-beta regulates the cell cycle status of interleukin-3 (IL-3) plus IL-1, stem cell factor, or IL-6 stimulated CD34+ human hematopoietic progenitor cells through different cell kinetic mechanisms depending on the applied.... Exp Hematol. 1994; 22(9):903-9. View

20.

Gothot A, van Der Loo J, Clapp D, Srour E . Cell cycle-related changes in repopulating capacity of human mobilized peripheral blood CD34(+) cells in non-obese diabetic/severe combined immune-deficient mice. Blood. 1998; 92(8):2641-9. View