c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation

Genes and Development - Tập 18 Số 22 - Trang 2747-2763 - 2004
Anne Wilson1, Mark Murphy2, Thórdur Óskarsson2, Konstantinos Kaloulis2, Michael D. Bettess2, Gabriela Oser2, Anne-Catherine Pasche2, Christian Knabenhans3, H. Robson MacDonald4, Andreas Trumpp5
1Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland.
2Swiss Institute for Experimental Cancer Research (ISREC)
3Swiss Federal Institute of Technology-Lausanne
4University of Lausanne
5Cell Biology and Tumor Biology

Tóm tắt

The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.

Từ khóa


Tài liệu tham khảo

10.1016/S1074-7613(01)00220-5

10.1101/sqb.1999.64.1

10.1038/35004599

1998, Front. Biosci., 3, D250, 10.2741/A239

10.1016/j.cell.2004.07.004

10.1016/S0960-9822(01)00154-3

10.1007/s002770100309

10.1634/stemcells.20-4-301

10.1101/gad.1024602

10.1016/S1534-5807(03)00160-6

10.1046/j.1365-2559.2002.01343.x

10.1016/S0962-8924(02)02352-8

10.1038/nature02040

10.1016/S0959-437X(00)00226-4

10.1126/science.287.5459.1804

10.1073/pnas.261562798

1999, Cancer Res., 59, 1685s

10.1016/0092-8674(90)90696-C

10.1016/S1074-7613(00)80643-3

1993, FASEB J., 7, 1475, 10.1096/fasebj.7.15.8262332

10.1084/jem.191.2.253

10.1101/gad928101

10.1016/0092-8674(93)90462-Y

10.1101/gad.906601

10.1016/S0092-8674(04)00255-7

10.1084/jem.183.4.1797

10.1146/annurev.cellbio.16.1.653

10.1126/science.281.5382.1509

10.1034/j.1600-065X.2002.18614.x

10.1083/jcb.141.2.515

10.1016/S0092-8674(02)00971-6

10.1126/science.1073823

10.1101/gad.13.20.2678

10.1126/science.1071489

10.1038/ncb0402-e101

10.1016/0092-8674(93)90251-K

10.1016/S0092-8674(00)80453-5

10.1146/annurev.immunol.21.120601.141007

10.1126/science.7660125

10.1016/S0301-472X(02)00883-4

10.1038/nrg952

10.1073/pnas.94.5.1908

10.1038/sj.onc.1207261

10.1182/blood.V97.8.2293

10.1038/nature01587

10.1016/S1097-2765(00)80350-0

10.1038/nrc904

10.1016/S0092-8674(02)00738-9

10.1038/ni984

10.1016/S1074-7613(00)80216-2

1990, Development, 110, 1001, 10.1242/dev.110.4.1001

1998, Blood, 91, 4099, 10.1182/blood.V91.11.4099

10.1006/dbio.1996.8443

10.1016/S1074-7613(00)80054-0

10.1126/science.1072530

10.1016/0092-8674(94)90383-2

1978, Blood Cells, 4, 7

10.1016/S0960-9822(99)80507-7

10.1038/ncb0402-e65

10.1073/pnas.88.7.2788

10.1073/pnas.232389399

10.1126/science.1069871

10.1073/pnas.2235735100

10.1038/35102160

10.1038/35070076

10.1073/pnas.242735899

10.1038/348331a0

10.1126/science.8140412

10.2307/3570892

Trentin J . 1970. Regulation of hematopoietic stem cells. Appleton-Century-Crofts, New York.

10.1101/gad.6.1.14

10.1038/414768a

10.1084/jem.175.1.175

1997, Blood, 90, 4354, 10.1182/blood.V90.11.4354

10.1016/S0092-8674(02)01014-0

10.1182/blood.V100.1.327

10.1359/jbmr.2001.16.12.2222

10.1182/blood-2003-11-4011

10.1038/88889

10.1016/S0962-8924(03)00003-5

10.1016/S1535-6108(03)00030-8

10.1093/emboj/cdf399

10.1126/science.287.5457.1427

10.1016/S0092-8674(00)81692-X

10.1146/annurev.cellbio.17.1.387

10.1016/S0962-8924(99)01559-7

10.1084/jem.194.7.1003

10.1038/nature02041

10.1002/bies.20052

Thông tin
Thông tin xuất bản

Genes and Development

Tập 18 Số 22

2747-2763

Thông tin tác giả