title: Loss of quiescence and impaired function of CD34(+)/CD38(low) cells one year following autologous stem cell transplantation.
abstract: Patients who have undergone autologous stem cell transplantation are subsequently more susceptible to chemotherapy-induced bone marrow toxicity. In the present study, bone marrow primitive progenitor cells were examined one year after autologous stem cell transplantation and compared with normal bone marrow and mobilized peripheral blood stem cells. Post-transplantation bone marrow contained a significantly lower percentage of quiescent cells in the CD34(+)/CD38(low) fraction compared to normal bone marrow. In addition, we observed a strong decrease in stem cell/primitive progenitor frequency in post-transplantation CD34(+) cells as defined by long-term culture assays. Measurement of the levels of reactive oxygen species by flow cytometry revealed comparable levels in post-transplantation and normal bone marrow CD34(+)/CD38(low) cells, while significantly higher levels of reactive oxygen species were observed in CD34(+)/CD38(high) cells following autologous stem cell transplantation compared to normal bone marrow. Moreover, post-transplantation CD34(+) bone marrow cells demonstrated an increased sensitivity to buthionine sulfoximine, a trigger for endogenous production of reactive oxygen species. Gene expression analysis on CD34(+) cells revealed a set of 195 genes, including HMOX1, EGR1, FOS and SIRPA that are persistently down-regulated in mobilized peripheral blood cells and post-transplantation bone marrow compared to normal bone marrow. In conclusion, our data indicate that the diminished regenerative capacity of bone marrow following autologous stem cell transplantation is possibly related to a loss of quiescence and a reduced tolerability to oxidative stress.
authors.affiliation: e.vellenga@umcg.nl.
authors.forename: Carolien M
authors.initials: CM
authors.lastname: Woolthuis
authors.forename: Annet Z
authors.initials: AZ
authors.lastname: Brouwers-Vos
authors.forename: Gerwin
authors.initials: G
authors.lastname: Huls
authors.forename: Joost Th M
authors.initials: JT
authors.lastname: de Wolf
authors.forename: Jan Jacob
authors.initials: JJ
authors.lastname: Schuringa
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000502:physiology*; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation / Q000639:trends*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014182:Transplantation, Autologous / Q000639:trends
chemical_list: D018952:Antigens, CD34; D017382:Reactive Oxygen Species; D051997:ADP-ribosyl Cyclase 1
references.citation: Blood. 2010 Jul 22;116(3):375-85
references.pmid: 20393133
references.citation: J Biol Chem. 1982 Nov 25;257(22):13704-12
references.pmid: 6128339
references.citation: Cell. 2007 Jan 26;128(2):325-39
references.pmid: 17254970
references.citation: Expert Rev Hematol. 2009 Aug;2(4):425-42
references.pmid: 21082947
references.citation: Eur J Cancer. 2004 May;40(8):1199-207
references.pmid: 15110884
references.citation: Blood. 2000 May 1;95(9):2829-37
references.pmid: 10779428
references.citation: Blood. 2008 Dec 1;112(12):4494-502
references.pmid: 18509090
references.citation: Nature. 2009 May 21;459(7245):387-392
references.pmid: 19404261
references.citation: Bone Marrow Transplant. 2011 Jan;46(1):110-5
references.pmid: 20383220
references.citation: Bone Marrow Transplant. 2001 May;27(9):959-66
references.pmid: 11436106
references.citation: Nat Immunol. 2007 Dec;8(12):1313-23
references.pmid: 17982459
references.citation: Blood. 2007 Oct 15;110(8):3056-63
references.pmid: 17595331
references.citation: Blood. 2001 Mar 15;97(6):1876-8
references.pmid: 11238132
references.citation: Blood. 2000 Jun 1;95(11):3289-96
references.pmid: 10828007
references.citation: Blood. 2010 Dec 9;116(24):5149-61
references.pmid: 20826720
references.citation: Blood. 2010 Feb 11;115(6):1113-20
references.pmid: 19880501
references.citation: Blood. 2000 Dec 15;96(13):4185-93
references.pmid: 11110690
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5431-6
references.pmid: 17374716
references.citation: Blood. 1998 Oct 15;92(8):2641-9
references.pmid: 9763545
references.citation: J Clin Oncol. 2005 Sep 20;23(27):6699-711
references.pmid: 16170178
references.citation: Curr Opin Genet Dev. 2009 Oct;19(5):461-8
references.pmid: 19811902
references.citation: Blood. 1995 Jun 1;85(11):3320-7
references.pmid: 7756665
references.citation: Blood. 2011 Sep 15;118(11):2941-50
references.pmid: 21734240
references.citation: Cancer Cell. 2011 Nov 15;20(5):591-605
references.pmid: 22094254
references.citation: Blood. 2008 Jan 15;111(2):537-43
references.pmid: 17971487
references.citation: Blood. 2007 Jul 15;110(2):719-26
references.pmid: 17420284
references.citation: J Clin Oncol. 2008 Dec 10;26(35):5775-82
references.pmid: 19001321
references.citation: N Engl J Med. 2011 Mar 17;364(11):1046-60
references.pmid: 21410373
references.citation: Cell Stem Cell. 2011 Oct 4;9(4):298-310
references.pmid: 21982230
references.citation: Cell Stem Cell. 2008 Apr 10;2(4):380-91
references.pmid: 18397757