The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells

被引：98

作者：

Ford, Anthony M. ^{[1
]}

Palmi, Chiara ^{[1
,2
,3
]}

Bueno, Clara ^{[1
,4
]}

Hong, Dengli

Cardus, Penny ^{[1
]}

Knight, Deborah ^{[1
]}

Cazzaniga, Giovanni ^{[2
]}

Enver, Tariq ^{[5
]}

Greaves, Mel ^{[1
]}

机构：

[1] Inst Canc Res, Sect Haematooncol, Sutton SM2 5NG, Surrey, England

[2] Univ Milano Bicocca, Pediat Clin, Ctr Ric Tettamanti, Osped San Gerardo, Monza, Italy

[3] Univ Vita Salute San Raffaele, PhD Program Mol Med, Milan, Italy

[4] Univ Granada, Andalusian Stem Cell Bank, Ctr Invest Biomed, Granada, Spain

[5] John Radcliffe Hosp, Weatherall Inst Mol Med, Mol Haematol Unit, Oxford OX3 9DU, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2009年 / 119卷 / 04期

关键词：

GROWTH-FACTOR-BETA; LYMPHOBLASTIC-LEUKEMIA; CHROMOSOME TRANSLOCATIONS; REPOPULATING CELLS; LENTIVIRAL VECTOR; STEM-CELLS; T(12/21); TRANSDUCTION; EXPRESSION; INHIBITOR;

D O I：

10.1172/JCI36428

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-beta. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-beta. Further analysis indicated that TEL-AML1 binds to a principal TGF-beta signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-beta-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34(+)CD38(-)CD19(+)) and a marked growth advantage in the presence of TGF-beta. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones.

引用

页码：826 / 836

页数：11

共 64 条

[1] Molecular evidence of lentiviral vector-mediated gene transfer into human self-renewing, multi-potent, long-term NOD/SCID repopulating hematopoietic cells [J].

Ailles, L ;

Schmidt, M ;

Santoni de Sio, FR ;

Glimm, H ;

Cavalieri, S ;

Bruno, S ;

Piacibello, W ;

Von Kalle, C ;

Naldini, L .

MOLECULAR THERAPY, 2002, 6 (05) :615-626

[2] The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo [J].

Andreasson, P ;

Schwaller, J ;

Anastasiadou, E ;

Aster, J ;

Gilliland, DG .

CANCER GENETICS AND CYTOGENETICS, 2001, 130 (02) :93-104

[3] Cancer and the chemokine network [J].

Balkwill, F .

NATURE REVIEWS CANCER, 2004, 4 (07) :540-550

[4]

Bernardin F, 2002, CANCER RES, V62, P3904

[5] TGFβ:: the molecular Jekyll and Hyde of cancer [J].

Bierie, Brian ;

Moses, Harold L. .

NATURE REVIEWS CANCER, 2006, 6 (07) :506-520

[6] ETV6 is the target of chromosome 12p deletions in t(12;21) childhood acute lymphocytic leukemia [J].

Cave, H ;

Cacheux, V ;

Raynaud, S ;

Brunie, G ;

Bakkus, M ;

Cochaux, P ;

Preudhomme, C ;

Lai, JL ;

Vilmer, E ;

Grandchamp, B .

LEUKEMIA, 1997, 11 (09) :1459-1464

[7] A NOVEL CELL-SURFACE MOLECULE ON EARLY B-LINEAGE CELLS [J].

COOPER, MD ;

MULVANEY, D ;

COUTINHO, A ;

CAZENAVE, PA .

NATURE, 1986, 321 (6070) :616-618

[8] Reduction in levels of the cyclin-dependent kinase inhibitor p27kip-1 coupled with transforming growth factor β neutralization induces cell-cycle entry and increases retroviral transduction of primitive human hematopoietic cells [J].

Dao, MA ;

Taylor, N ;

Nolta, JA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (22) :13006-13011

[9] Loss of functional cell surface transforming growth factor beta (TGF-beta) type 1 receptor correlates with insensitivity to TGF-beta in chronic lymphocytic leukemia [J].

DeCoteau, JF ;

Knaus, PI ;

Yankelev, H ;

Reis, MD ;

Lowsky, R ;

Lodish, HF ;

Kadin, ME .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (11) :5877-5881

[10] High-level transduction and gene expression in hematopoietic repopulating cells using a human imunodeficiency virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter [J].

Demaison, C ;

Parsley, K ;

Brouns, G ;

Scherr, M ;

Battmer, K ;

Kinnon, C ;

Grez, M ;

Thrasher, AJ .

HUMAN GENE THERAPY, 2002, 13 (07) :803-813

← 1 2 3 4 5 6 7 →