A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice

Yinfei Tan, Roman A. Timakhov, Mamta Rao, Deborah A. Altomare, Jinfei Xu, Zemin Liu, Qingshen Gao, Suresh C. Jhanwar, Antonio Di Cristofano, David L. Wiest, Janice E. Knepper, Joseph R. Testa

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The oncogene v-akt was isolated from a retrovirus that induced murine thymic lymphomas. Transgenic mice expressing a constitutively activated form of the cellular homologue Akt2 specifically in immature T cells develop spontaneous thymic lymphomas. We hypothesized that tumors from these mice might exhibit oncogenic chromosomal rearrangements that cooperate with activated Akt2 in lymphomagenesis. Cytogenetic analysis revealed a recurrent clonal inversion of chromosome 6, inv(6), in thymic lymphomas from multiple transgenic founder lines, including one line in which 15 of 15 primary tumors exhibited this same rearrangement. Combined fluorescence in situ hybridization, PCR, and DNA sequence analyses showed that the distal inv(6) breakpoint resides at the T-cell receptor β chain locus, Tcrb. The proximal breakpoint maps to a region near a locus comprising the linked homeobox/transcription factor genes Dlx5 and Dlx6. Expression analysis of genes translocated to the vicinity of the Tcrb enhancer revealed that Dlx5 and Dlx6 are overexpressed in tumors exhibiting the inv(6). Experimental overexpression of Dlx5 in mammalian cells resulted in enhanced cell proliferation and increased colony formation, and clonogenic assays revealed cooperativity when both Dlx5 and activated Akt2 were coexpressed. In addition, DLX5, but not DLX6, was found to be abundantly expressed in three of seven human T-cell lymphomas tested. These findings suggest that the Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis.

Original languageEnglish (US)
Pages (from-to)1296-1302
Number of pages7
JournalCancer Research
Volume68
Issue number5
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

Fingerprint

T-Cell Lymphoma
Homeobox Genes
Transgenic Mice
Lymphoma
Oncogenes
Neoplasms
Chromosomes, Human, Pair 6
Cytogenetic Analysis
Retroviridae
T-Cell Antigen Receptor
Fluorescence In Situ Hybridization
DNA Sequence Analysis
Transcription Factors
Cell Proliferation
T-Lymphocytes
Gene Expression
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice. / Tan, Yinfei; Timakhov, Roman A.; Rao, Mamta; Altomare, Deborah A.; Xu, Jinfei; Liu, Zemin; Gao, Qingshen; Jhanwar, Suresh C.; Di Cristofano, Antonio; Wiest, David L.; Knepper, Janice E.; Testa, Joseph R.

In: Cancer Research, Vol. 68, No. 5, 01.03.2008, p. 1296-1302.

Research output: Contribution to journalArticle

Tan, Y, Timakhov, RA, Rao, M, Altomare, DA, Xu, J, Liu, Z, Gao, Q, Jhanwar, SC, Di Cristofano, A, Wiest, DL, Knepper, JE & Testa, JR 2008, 'A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice', Cancer Research, vol. 68, no. 5, pp. 1296-1302. https://doi.org/10.1158/0008-5472.CAN-07-3218
Tan, Yinfei ; Timakhov, Roman A. ; Rao, Mamta ; Altomare, Deborah A. ; Xu, Jinfei ; Liu, Zemin ; Gao, Qingshen ; Jhanwar, Suresh C. ; Di Cristofano, Antonio ; Wiest, David L. ; Knepper, Janice E. ; Testa, Joseph R. / A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice. In: Cancer Research. 2008 ; Vol. 68, No. 5. pp. 1296-1302.
@article{49f6ddf8a10844c4bc7dfda88501d28b,
title = "A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice",
abstract = "The oncogene v-akt was isolated from a retrovirus that induced murine thymic lymphomas. Transgenic mice expressing a constitutively activated form of the cellular homologue Akt2 specifically in immature T cells develop spontaneous thymic lymphomas. We hypothesized that tumors from these mice might exhibit oncogenic chromosomal rearrangements that cooperate with activated Akt2 in lymphomagenesis. Cytogenetic analysis revealed a recurrent clonal inversion of chromosome 6, inv(6), in thymic lymphomas from multiple transgenic founder lines, including one line in which 15 of 15 primary tumors exhibited this same rearrangement. Combined fluorescence in situ hybridization, PCR, and DNA sequence analyses showed that the distal inv(6) breakpoint resides at the T-cell receptor β chain locus, Tcrb. The proximal breakpoint maps to a region near a locus comprising the linked homeobox/transcription factor genes Dlx5 and Dlx6. Expression analysis of genes translocated to the vicinity of the Tcrb enhancer revealed that Dlx5 and Dlx6 are overexpressed in tumors exhibiting the inv(6). Experimental overexpression of Dlx5 in mammalian cells resulted in enhanced cell proliferation and increased colony formation, and clonogenic assays revealed cooperativity when both Dlx5 and activated Akt2 were coexpressed. In addition, DLX5, but not DLX6, was found to be abundantly expressed in three of seven human T-cell lymphomas tested. These findings suggest that the Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis.",
author = "Yinfei Tan and Timakhov, {Roman A.} and Mamta Rao and Altomare, {Deborah A.} and Jinfei Xu and Zemin Liu and Qingshen Gao and Jhanwar, {Suresh C.} and {Di Cristofano}, Antonio and Wiest, {David L.} and Knepper, {Janice E.} and Testa, {Joseph R.}",
year = "2008",
month = "3",
day = "1",
doi = "10.1158/0008-5472.CAN-07-3218",
language = "English (US)",
volume = "68",
pages = "1296--1302",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice

AU - Tan, Yinfei

AU - Timakhov, Roman A.

AU - Rao, Mamta

AU - Altomare, Deborah A.

AU - Xu, Jinfei

AU - Liu, Zemin

AU - Gao, Qingshen

AU - Jhanwar, Suresh C.

AU - Di Cristofano, Antonio

AU - Wiest, David L.

AU - Knepper, Janice E.

AU - Testa, Joseph R.

PY - 2008/3/1

Y1 - 2008/3/1

N2 - The oncogene v-akt was isolated from a retrovirus that induced murine thymic lymphomas. Transgenic mice expressing a constitutively activated form of the cellular homologue Akt2 specifically in immature T cells develop spontaneous thymic lymphomas. We hypothesized that tumors from these mice might exhibit oncogenic chromosomal rearrangements that cooperate with activated Akt2 in lymphomagenesis. Cytogenetic analysis revealed a recurrent clonal inversion of chromosome 6, inv(6), in thymic lymphomas from multiple transgenic founder lines, including one line in which 15 of 15 primary tumors exhibited this same rearrangement. Combined fluorescence in situ hybridization, PCR, and DNA sequence analyses showed that the distal inv(6) breakpoint resides at the T-cell receptor β chain locus, Tcrb. The proximal breakpoint maps to a region near a locus comprising the linked homeobox/transcription factor genes Dlx5 and Dlx6. Expression analysis of genes translocated to the vicinity of the Tcrb enhancer revealed that Dlx5 and Dlx6 are overexpressed in tumors exhibiting the inv(6). Experimental overexpression of Dlx5 in mammalian cells resulted in enhanced cell proliferation and increased colony formation, and clonogenic assays revealed cooperativity when both Dlx5 and activated Akt2 were coexpressed. In addition, DLX5, but not DLX6, was found to be abundantly expressed in three of seven human T-cell lymphomas tested. These findings suggest that the Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis.

AB - The oncogene v-akt was isolated from a retrovirus that induced murine thymic lymphomas. Transgenic mice expressing a constitutively activated form of the cellular homologue Akt2 specifically in immature T cells develop spontaneous thymic lymphomas. We hypothesized that tumors from these mice might exhibit oncogenic chromosomal rearrangements that cooperate with activated Akt2 in lymphomagenesis. Cytogenetic analysis revealed a recurrent clonal inversion of chromosome 6, inv(6), in thymic lymphomas from multiple transgenic founder lines, including one line in which 15 of 15 primary tumors exhibited this same rearrangement. Combined fluorescence in situ hybridization, PCR, and DNA sequence analyses showed that the distal inv(6) breakpoint resides at the T-cell receptor β chain locus, Tcrb. The proximal breakpoint maps to a region near a locus comprising the linked homeobox/transcription factor genes Dlx5 and Dlx6. Expression analysis of genes translocated to the vicinity of the Tcrb enhancer revealed that Dlx5 and Dlx6 are overexpressed in tumors exhibiting the inv(6). Experimental overexpression of Dlx5 in mammalian cells resulted in enhanced cell proliferation and increased colony formation, and clonogenic assays revealed cooperativity when both Dlx5 and activated Akt2 were coexpressed. In addition, DLX5, but not DLX6, was found to be abundantly expressed in three of seven human T-cell lymphomas tested. These findings suggest that the Dlx5 can act as an oncogene by cooperating with Akt2 to promote lymphomagenesis.

UR - http://www.scopus.com/inward/record.url?scp=40449083102&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40449083102&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-07-3218

DO - 10.1158/0008-5472.CAN-07-3218

M3 - Article

C2 - 18316591

AN - SCOPUS:40449083102

VL - 68

SP - 1296

EP - 1302

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 5

ER -