The Wnt/β-Catenin Pathway Is Required for the Development of Leukemia Stem Cells in AML

被引：610

作者：

Wang, Yingzi ^{[1
]}

Krivtsov, Andrei V. ^{[1
]}

Sinha, Amit U. ^{[1
,2
]}

North, Trista E. ^{[3
,4
]}

Goessling, Wolfram ^{[4
,5
,6
]}

Feng, Zhaohui ^{[1
,2
]}

Zon, Leonard I. ^{[1
,4
,7
]}

Armstrong, Scott A. ^{[1
,2
,4
]}

机构：

[1] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Beth Israel Deaconess Hosp, Dept Pathol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[7] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

SCIENCE | 2010年 / 327卷 / 5973期

关键词：

ACUTE MYELOID-LEUKEMIA; BETA-CATENIN; COLON-CANCER; HEMATOPOIETIC-CELLS; SIGNALING PATHWAY; IN-VIVO; PROGENITORS; EXPRESSION; EXPANSION; RENEWAL;

D O I：

10.1126/science.1186624

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/beta-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/beta-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. beta-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in AML.

引用

页码：1650 / 1653

页数：4

共 25 条

[1] Hox genes:: From leukemia-to hematopoietic stem cell expansion [J].

Abramovich, C ;

Pineault, N ;

Ohta, PH ;

Humphries, RK .

HEMATOPOIETIC STEM CELLS V, 2005, 1044 :109-116

[2] Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell [J].

Bonnet, D ;

Dick, JE .

NATURE MEDICINE, 1997, 3 (07) :730-737

[3]

Brault V, 2001, DEVELOPMENT, V128, P1253

[4] Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-β-catenin signaling axis [J].

Castellone, MD ;

Teramoto, H ;

Williams, BO ;

Druey, KM ;

Gutkind, JS .

SCIENCE, 2005, 310 (5753) :1504-1510

[5] β-catenin is dispensable for hematopoiesis and lymphopoiesis [J].

Cobas, M ;

Wilson, A ;

Ernst, B ;

Mancini, JC ;

MacDonald, HR ;

Kemler, R ;

Radtke, F .

JOURNAL OF EXPERIMENTAL MEDICINE, 2004, 199 (02) :221-229

[6] Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors [J].

Cozzio, A ;

Passegué, E ;

Ayton, PM ;

Karsunky, H ;

Cleary, ML ;

Weissman, IL .

GENES & DEVELOPMENT, 2003, 17 (24) :3029-3035

[7] Stem cell concepts renew cancer research [J].

Dick, John E. .

BLOOD, 2008, 112 (13) :4793-4807

[8] The role of cyclooxygenase-2 and prostaglandins in colon cancer [J].

Eisinger, Annie L. ;

Prescott, Stephen M. ;

Jones, David A. ;

Stafforini, Diana M. .

PROSTAGLANDINS & OTHER LIPID MEDIATORS, 2007, 82 (1-4) :147-154

[9] Genetic Interaction of PGE2 and Wnt Signaling Regulates Developmental Specification of Stem Cells and Regeneration [J].

Goessling, Wolfram ;

North, Trista E. ;

Loewer, Sabine ;

Lord, Allegra M. ;

Lee, Sang ;

Stoick-Cooper, Cristi L. ;

Weidinger, Gilbert ;

Puder, Mark ;

Daley, George Q. ;

Moon, Randall T. ;

Zon, Leonard I. .

CELL, 2009, 136 (06) :1136-1147

[10] MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors [J].

Huntly, BJP ;

Shigematsu, H ;

Deguchi, K ;

Lee, BH ;

Mizuno, S ;

Duclos, N ;

Rowan, R ;

Amaral, S ;

Curley, D ;

Williams, IR ;

Akashi, K ;

Gilliland, DG .

CANCER CELL, 2004, 6 (06) :587-596

← 1 2 3 →