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Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

Item Type:Article
Title:Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma
Creators Name:Mathas, S. and Kreher, S. and Meaburn, K.J. and Joehrens, K. and Lamprecht, B. and Assaf, C. and Sterry, W. and Kadin, M.E. and Daibata, M. and Joos, S. and Hummel, M. and Stein, H. and Janz, M. and Anagnostopoulos, I. and Schrock, E. and Misteli, T. and Doerken, B.
Abstract:Although the identification and characterization of translocations have rapidly increased, little is known about the mechanisms of how translocations occur in vivo. We used anaplastic large cell lymphoma (ALCL) with and without the characteristic t(2;5)(p23;q35) translocation to study the mechanisms of formation of translocations and of ALCL transformation. We report deregulation of several genes located near the ALCL translocation breakpoint, regardless of whether the tumor contains the t(2;5). The affected genes include the oncogenic transcription factor Fra2 (located on 2p23), the HLH protein Id2 (2p25), and the oncogenic tyrosine kinase CSF1-receptor (5q33.1). Their up-regulation promotes cell survival and repression of T cell-specific gene expression programs that are characteristic for ALCL. The deregulated genes are in spatial proximity within the nuclear space of t(2;5)-negative ALCL cells, facilitating their translocation on induction of double-strand breaks. These data suggest that deregulation of breakpoint-proximal genes occurs before the formation of translocations, and that aberrant transcriptional activity of genomic regions is linked to their propensity to undergo chromosomal translocations. Also, our data demonstrate that deregulation of breakpoint-proximal genes has a key role in ALCL.
Keywords:Cancer Genetics, Signal Transduction, Nuclear Architecture, Lymphomatoid Papulosis
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:106
Number:14
Page Range:5831-5836
Date:7 April 2009
Additional Information:Copyright (c) 2009 by The National Academy of Sciences
Official Publication:https://doi.org/10.1073/pnas.0900912106
PubMed:View item in PubMed

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