Various Types of Rearrangements Target TLX3 Locus in T-Cell Acute Lymphoblastic Leukemia XinYing Su, 1 Maryvonne Busson, 1 Ve´ ronique Della Valle, 1 Paola Ballerini, 2 Nicole Dastugue, 3 Pascaline Talmant, 4 Adolfo A. Ferrando, 5 Dominique Baudry-Bluteau, 1 Serge Romana, 1 Roland Berger, 1 and Olivier A. Bernard 1 * 1 INSERM E0210, IRNEM, Hoˆ pital Necker, Paris, France 2 Service d’He´matologie Biologique, Hoˆ pital d’Enfants Armand Trousseau, Paris, France 3 Laboratoire d’He´matologie, Hoˆ pital Purpan, Toulouse, France 4 Laboratoire de Cytoge´ne´tique, Hotel Dieu, Nantes, France 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts Most chromosomal translocations observed in T-cell acute lymphoblastic leukemia (T-ALL) often produce transcriptional activation of transcription factor oncogenes. Ectopic expression of the TLX3 (also known as HOX11L2) gene has been shown to be associated with a cryptic t(5;14)(q35;q32) translocation specific for a subtype of T-ALL. Here we report several examples of variant and alternative translocations resulting in expression of TLX3 in T-ALL, and we describe three of these translocations in detail. In particular, the CDK6 gene was rearranged in two t(5;7)(q35;q21) translocations. In two additional instances, fusion of the BCL11B (also known as CTIP2) and RANBP17/TLX3 loci were shown to result from subtle genomic insertion/deletion within these loci. This study further underscores that TLX3 expression in T-ALL is strongly associated with the presence of genomic rearrangements. © 2004 Wiley-Liss, Inc. INTRODUCTION Transcriptional deregulation is a common theme in human T-cell acute lymphoblastic leukemia (T- ALL). Two members of the orphan homeobox transcription factor TLX (also known as HOX11) family have been shown to be expressed ectopi- cally as a result of chromosomal translocations af- fecting the TLX1 (also known as HOX11) and TCRA/TCRD genes in the t(10;14)(q24;q11) translocation and the TLX3 and BCL11B (also know as CTIP2) gene in the t(5;14)(q35;q32) translocation (Lichty et al., 1995; Bernard et al., 2001). Apart from these major translocations, al- ternative, less frequent abnormalities have been observed, such as the t(7;10)(q35;q24) transloca- tion affecting TLX1 and TCRB (Kennedy et al., 1991) and the t(5;14)(q35;q11) translocation af- fecting TLX3 and TCRA/TCRD (Hansen-Hagge et al., 2002). Recent work combining cytogenetic and molecular studies of T-ALL samples has suggested that TLX1 and TLX3 expression could occur independently of chromosomal abnormali- ties (Ballerini et al., 2002; Ferrando et al., 2002; Berger et al., 2003; Kees et al., 2003; Cave et al., 2004; Ferrando et al., 2004). We now describe additional examples of genomic abnormalities leading to transcriptional activation of TLX3, some of which can easily be overlooked by clas- sical cytogenetics studies. MATERIALS AND METHODS Patients Hematological, immunophenotypic, and conven- tional karyotypic data on 5 children with T-ALL and the lymphoblastic cell line DND41, estab- lished from a 13-year-old boy with T-ALL, are given in Table 1. Samples from the patients were obtained after informed consent of their parents. Cytogenetics Chromosome studies using RHG- and GTG- banding techniques were performed on bone mar- row cells. The description of chromosomal changes followed ISCN recommendations (ISCN 1995). FISH Analysis Metaphase fluorescence in situ hybridization (FISH) analysis was performed as previously described (Ro- Supported by: INSERM; Ligue Nationale contre le Cancer (LNCC); Comite´ de Paris de la Ligue Nationale Contre le Cancer (LNCC-CP); Fondation pour la Recherche Me´ dicale (FRM); Asso- ciation Franco-Chinoise (to X.Y.S.); Association pour la Recherche sur le Cancer (to X.Y.S.). *Correspondence to: Olivier A. Bernard, INSERM EMI 0210, Tour Pasteur, Hoˆ pital Necker, 149 rue de Se` vres, 75015 Paris, France. E-mail: olivier.bernard@necker.fr Received 5 April 2004; Accepted 29 June 2004 DOI 10.1002/gcc.20088 Published online 11 August 2004 in Wiley InterScience (www.interscience.wiley.com). GENES, CHROMOSOMES & CANCER 41:243–249 (2004) © 2004 Wiley-Liss, Inc.