Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations

Brian B. Haines; Chun Jeih Ryu; Sandy Chang; Alexei Protopopov; Andreas Luch; Yun Hee Kang; Dobrin D. Draganov; Maria F. Fragoso; Sang Gi Paik; Hyo Jeong Hong; Ronald A. DePinho; Jianzhu Chen

doi:10.1016/j.ccr.2006.01.004

Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations

Brian B. Haines, Chun Jeih Ryu, Sandy Chang, Alexei Protopopov, Andreas Luch, Yun Hee Kang, Dobrin D. Draganov, Maria F. Fragoso, Sang Gi Paik, Hyo Jeong Hong, Ronald A. DePinho, Jianzhu Chen

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR β gene enhancer (Eβ) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eβ mutation into p53^-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.

Original language	English (US)
Pages (from-to)	109-120
Number of pages	12
Journal	Cancer cell
Volume	9
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2006.01.004
State	Published - Feb 2006
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Access to Document

10.1016/j.ccr.2006.01.004

Cite this

Haines, B. B., Ryu, C. J., Chang, S., Protopopov, A., Luch, A., Kang, Y. H., Draganov, D. D., Fragoso, M. F., Paik, S. G., Hong, H. J., DePinho, R. A., & Chen, J. (2006). Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations. Cancer cell, 9(2), 109-120. https://doi.org/10.1016/j.ccr.2006.01.004

Haines, BB, Ryu, CJ, Chang, S, Protopopov, A, Luch, A, Kang, YH, Draganov, DD, Fragoso, MF, Paik, SG, Hong, HJ, DePinho, RA & Chen, J 2006, 'Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations', Cancer cell, vol. 9, no. 2, pp. 109-120. https://doi.org/10.1016/j.ccr.2006.01.004

@article{10ad3465a3274decb5bdf482b7a71709,

title = "Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations",

abstract = "Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR β gene enhancer (Eβ) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eβ mutation into p53-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.",

author = "Haines, {Brian B.} and Ryu, {Chun Jeih} and Sandy Chang and Alexei Protopopov and Andreas Luch and Kang, {Yun Hee} and Draganov, {Dobrin D.} and Fragoso, {Maria F.} and Paik, {Sang Gi} and Hong, {Hyo Jeong} and DePinho, {Ronald A.} and Jianzhu Chen",

note = "Funding Information: We thank Dr. Tyler Jacks for p53 −/− mice, Drs. Herman N. Eisen and Tania Baker for manuscript review, and members of the Chen laboratory for helpful discussions. This work was supported in part by grants AI40416 and CA100875 from the National Institutes of Health and David Koch Research Fund (to J.C.), a Cancer Center Core Grant (to Tyler Jacks), a grant from Korea Science and Engineering Foundation (R01-2004-000-10047-0 to C.J.R.), and a grant from the Nano-Bio Research and Development Program of the Ministry of Science and Technology, Korea (TNM0200512 to H.J.H.). S.C. is supported by the Ellison Medical Foundation, NIH grant AG01019, and a Belfer Cancer Core grant to the DFCI. R.A.D. is an American Cancer Society Research Professor and an Ellison Foundation Senior Scholar and is supported by grants from the NIH and ACS. B.B.H. was partly supported by a Postdoctoral Fellowship from the American Cancer Society (PF0122801), and A.L. was partly supported by a Research Fellowship from the Deutsche Forschungsgemeinschaft (LU 841/2-1). Array CGH profiles were performed at the Arthur and Rochelle Belfer Cancer Genomic Center at the Dana-Farber Cancer Institute. ",

year = "2006",

month = feb,

doi = "10.1016/j.ccr.2006.01.004",

language = "English (US)",

volume = "9",

pages = "109--120",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations

AU - Haines, Brian B.

AU - Ryu, Chun Jeih

AU - Chang, Sandy

AU - Protopopov, Alexei

AU - Luch, Andreas

AU - Kang, Yun Hee

AU - Draganov, Dobrin D.

AU - Fragoso, Maria F.

AU - Paik, Sang Gi

AU - Hong, Hyo Jeong

AU - DePinho, Ronald A.

AU - Chen, Jianzhu

N1 - Funding Information: We thank Dr. Tyler Jacks for p53 −/− mice, Drs. Herman N. Eisen and Tania Baker for manuscript review, and members of the Chen laboratory for helpful discussions. This work was supported in part by grants AI40416 and CA100875 from the National Institutes of Health and David Koch Research Fund (to J.C.), a Cancer Center Core Grant (to Tyler Jacks), a grant from Korea Science and Engineering Foundation (R01-2004-000-10047-0 to C.J.R.), and a grant from the Nano-Bio Research and Development Program of the Ministry of Science and Technology, Korea (TNM0200512 to H.J.H.). S.C. is supported by the Ellison Medical Foundation, NIH grant AG01019, and a Belfer Cancer Core grant to the DFCI. R.A.D. is an American Cancer Society Research Professor and an Ellison Foundation Senior Scholar and is supported by grants from the NIH and ACS. B.B.H. was partly supported by a Postdoctoral Fellowship from the American Cancer Society (PF0122801), and A.L. was partly supported by a Research Fellowship from the Deutsche Forschungsgemeinschaft (LU 841/2-1). Array CGH profiles were performed at the Arthur and Rochelle Belfer Cancer Genomic Center at the Dana-Farber Cancer Institute.

PY - 2006/2

Y1 - 2006/2

N2 - Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR β gene enhancer (Eβ) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eβ mutation into p53-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.

AB - Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR β gene enhancer (Eβ) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the Eβ mutation into p53-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.

UR - http://www.scopus.com/inward/record.url?scp=32044441425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=32044441425&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2006.01.004

DO - 10.1016/j.ccr.2006.01.004

M3 - Article

C2 - 16473278

AN - SCOPUS:32044441425

SN - 1535-6108

VL - 9

SP - 109

EP - 120

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this