Overexpression of Rheb2 enhances mouse hematopoietic progenitor cell growth while impairing stem cell repopulation.
Molecular mechanisms preserving hematopoietic stem cell (HSC) self-renewal by maintaining a balance between proliferation, differentiation, and other processes are not fully understood. Hyperactivation of the mammalian target of rapamycin (mTOR) pathway, causing sustained proliferative signals, can lead to exhaustion of HSC repopulating ability. We examined the role of the novel ras gene Rheb2, an activator of the mTOR kinase, in colony-forming ability, survival, and repopulation of immature mouse hematopoietic cells. In a cell line model of mouse hematopoietic progenitor cells (HPCs), we found enhanced proliferation and mTOR signaling in cells overexpressing Rheb2. In addition, overexpression of Rheb2 enhanced colony-forming ability and survival of primary mouse bone marrow HPCs. Expansion of phenotypic HSCs in vitro was enhanced by Rheb2 overexpression. Consistent with these findings, Rheb2 overexpression transiently expanded phenotypically defined immature hematopoietic cells after in vivo transplantation; however, these Rheb2-transduced cells were significantly impaired in overall repopulation of primary and secondary congenic transplantation recipients. Our findings suggest that HPCs and HSCs behave differently in response to growth-promoting signals stimulated by Rheb2. These results may have value in elucidating mechanisms controlling the balance between proliferation and repopulating ability, a finding of importance in clinical uses of HPCs/HSCs.
Campbell
Timothy B
TB
Department of Microbiology and Immunology, Indiana University School of Medicine, Walther Oncology Center, Indianapolis, IN 46202-5181, USA.
Basu
Sunanda
S
Hangoc
Giao
G
Tao
Wen
W
Broxmeyer
Hal E
HE
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014184:Transplantation, Homologous
D002352:Carrier Proteins; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins
Oncogene. 2004 Apr 19;23(18):3151-71
15094765
Science. 2002 Oct 18;298(5593):601-4
12228721
EMBO J. 2004 Oct 13;23(20):4116-25
15385956
Cancer Res. 2007 May 1;67(9):4287-94
17483341
Leukemia. 2005 Jan;19(1):98-102
15496972
J Exp Med. 2005 Apr 18;201(8):1307-18
15837815
Exp Hematol. 2006 Sep;34(9):1230-9
16939816
Exp Hematol. 2004 Sep;32(9):852-60
15345287
Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):597-602
14699048
FEBS Lett. 2005 Aug 29;579(21):4763-8
16098514
Mol Biol Rep. 2005 Dec;32(4):205-14
16328882
J Biol Chem. 2005 Sep 2;280(35):31101-8
16006564
Stem Cells. 2006 Jan;24(1):105-14
16123382
Cell Mol Life Sci. 2000 Dec;57(13-14):1950-63
11215520
J Leukoc Biol. 2003 May;73(5):630-8
12714578
Blood. 1999 Mar 15;93(6):2043-56
10068678
Blood. 2005 May 1;105(9):3538-41
15644420
Cancer Cell. 2004 Apr;5(4):375-87
15093544
J Immunol. 2003 Jan 1;170(1):421-9
12496427
Leukemia. 2005 Dec;19(12):2153-8
16193082
Gene Ther. 2004 Jan;11(1):61-9
14681698
Blood. 2005 Dec 15;106(13):4261-8
16150937
Blood. 2007 May 1;109(9):3945-52
17192389
J Leukoc Biol. 2005 Dec;78(6):1378-85
16204634
Blood. 2006 Mar 15;107(6):2303-10
16282343
J Exp Med. 2005 Dec 5;202(11):1599-611
16330818
Nature. 2006 May 25;441(7092):475-82
16598206
Science. 2004 Aug 13;305(5686):1000-3
15310902
Cell. 2006 Feb 10;124(3):471-84
16469695
J Biol Chem. 2004 Jul 16;279(29):29930-7
15150271
Science. 2000 Mar 10;287(5459):1804-8
10710306