TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemia

被引：130

作者：

Sabaawy, Hatem E. ^{[1
]}

Azuma, Mizuki

Embree, Lisa J.

Tsai, Huai-Jen

Starost, Matthew F.

Hickstein, Dennis D.

机构：

[1] NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, Bethesda, MD 20892 USA

[2] Natl Taiwan Univ, Inst Mol & Cellular Biol, Taipei 10617, Taiwan

[3] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2006年 / 103卷 / 41期

关键词：

stem cell; translocation; childhood cancer; genetics;

D O I：

10.1073/pnas.0603349103

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：

Acute lymphoblastic leukemia (ALL) is a clonal disease that evolves through the accrual of genetic rearrangements and/or mutations within the dominant clone. The TEL-AML1 (ETV6-RUNX1) fusion in precursor-B (pre-B) ALL is the most common genetic rearrangement in childhood cancer; however, the cellular origin and the molecular pathogenesis of TEL-AML1-induced leukemia have not been identified. To study the origin of TEL-AML1-induced ALL, we generated transgenic zebrafish expressing TEL-AML1 either ubiquitously or in lymphoid progenitors. TEL-AML1 expression in all lineages, but not lymphoid-restricted expression, led to progenitor cell expansion that evolved into oligoclonal B-lineage ALL in 3% of the transgenic zebrafish. This leukemia was transplantable to conditioned wildtype recipients. We demonstrate that TEL-AML1 induces a B cell differentiation arrest, and that leukemia development is associated with loss of TEL expression and elevated Bcl2/Bax ratio. The TEL-AML1 transgenic zebrafish models human pre-B ALL, identifies the molecular pathways associated with leukemia development, and serves as the foundation for subsequent genetic screens to identify modifiers and leukemia therapeutic targets.

引用

页码：15166 / 15171

页数：6

共 48 条

[1] 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

[2] Myelopoiesis in the zebrafish, Danio rerio [J].

Bennett, CM ;

Kanki, JP ;

Rhodes, J ;

Liu, TX ;

Paw, BH ;

Kieran, MW ;

Langenau, DM ;

Delahaye-Brown, A ;

Zon, LI ;

Fleming, MD ;

Look, AT .

BLOOD, 2001, 98 (03) :643-651

[3]

Bernardin F, 2002, CANCER RES, V62, P3904

[4] Isolation and characterization of runxa and runxb, zebrafish members of the runt family of transcriptional regulators [J].

Burns, CE ;

DeBlasio, T ;

Zhou, Y ;

Zhang, J ;

Zon, L ;

Nimer, SD .

EXPERIMENTAL HEMATOLOGY, 2002, 30 (12) :1381-1389

[5] Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model [J].

Fischer, M ;

Schwieger, M ;

Horn, S ;

Niebuhr, B ;

Ford, A ;

Roscher, S ;

Bergholz, U ;

Greaves, M ;

Löhler, J ;

Stocking, C .

ONCOGENE, 2005, 24 (51) :7579-7591

[6] One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus [J].

Gilley, J ;

Fried, M .

ONCOGENE, 2001, 20 (50) :7447-7452

[7] FUSION OF THE TEL GENE ON 12P13 TO THE AML1 GENE ON 21Q22 IN ACUTE LYMPHOBLASTIC-LEUKEMIA [J].

GOLUB, TR ;

BARKER, GF ;

BOHLANDER, SK ;

HIEBERT, SW ;

WARD, DC ;

BRAYWARD, P ;

MORGAN, E ;

RAIMONDI, SC ;

ROWLEY, JD ;

GILLILAND, DG .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (11) :4917-4921

[8] A matter of life and death [J].

Green, DR ;

Evan, GI .

CANCER CELL, 2002, 1 (01) :19-30

[9] TEL/AML1 shows dominant-negative effects over TEL as well as AML1 [J].

Gunji, H ;

Waga, K ;

Nakamura, F ;

Maki, K ;

Sasaki, K ;

Nakamura, Y ;

Mitani, K .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 322 (02) :623-630

[10] RESOLUTION AND CHARACTERIZATION OF PRO-B AND PRE-PRO-B CELL STAGES IN NORMAL MOUSE BONE-MARROW [J].

HARDY, RR ;

CARMACK, CE ;

SHINTON, SA ;

KEMP, JD ;

HAYAKAWA, K .

JOURNAL OF EXPERIMENTAL MEDICINE, 1991, 173 (05) :1213-1225

← 1 2 3 4 5 →