A Complex Pattern of Recurrent Chromosomal Losses and Gains in T-Cell Prolymphocytic Leukemia Jean Soulier, 1,2 * Gae ¨ lle Pierron, 2 Danielle Vecchione, 2 Richard Garand, 3 Franc ¸oise Brizard, 4 Franc ¸ois Sigaux, 2 Marc-Henri Stern, 2 and Alain Aurias 1 1 Unite ´ INSERM U509, Laboratoire de Pathologie Mole ´culaire des Cancers, Institut Curie, Paris, France 2 Unite ´ INSERM U462, Laboratoire Associe ´ Number 10 du Comite ´ de Paris de la Ligue Nationale Contre le Cancer, et Laboratoire Central d’He ´matologie, Institut Universitaire d’He ´matologie, Ho ˆ pital Saint Louis, Paris, France 3 Laboratoire d’He ´matologie, CHU de Nantes, Nantes, France 4 Laboratoire d’He ´matologie, CHU de Poitiers, Poitiers, France T-cell prolymphocytic leukemia (T-PLL) is a rare malignant proliferation of lymphoid cells with a postthymic phenotype. Previous cytogenetic and molecular studies reported complex karyotypes with recurrent chromosomal abnormalities, including translocations involving either TCL1 at 14q32.1 or MTCP1 at Xq28, inactivation of the ATM gene by deletion and/or mutation, and isochromosomes 8. For extensive study of chromosomal imbalances in T-PLL, we analyzed 22 tumoral DNAs using comparative genomic hybridization (CGH). Abnormal CGH profiles were detected in all cases, demonstrating highly recurrent gains and losses and largely extending the abnormalities previously established. Only a few nonrecurrent abnor- malities were observed, in contrast to the genetic instability anticipated from ATM inactivation. Nine recurrent regions of loss were identified at 8p (frequency 86%), 11q (68%), 22q11 (45%), 13q (41%), 6q (36%), 9p (27%), 12p (23%), 11p11–p14 (23%), and 17p (23%), as well as four regions of gain at 8q (82%), 14q32 (50%), 22q21– qter (41%), and 6p (23%). Several recurrent chromosomal abnormalities were simultaneously present in each case (mean, 5.7; up to 10), none being mutually exclusive of another. Fluorescence in situ hybridization analysis confirmed and extended 22q11 and 13q losses, giving final frequencies of 55% and 45%, respectively. Analysis of one case over a 7-year period confirmed the overall genetic stability of T-PLL and showed that tumor progression was associated with the onset of a few chromosomal abnormalities. This study establishes a complex pattern of highly recurrent chromosomal abnormalities in T-PLL, including some, such as chromosome 13 deletion, commonly found in other lymphoid malignancies. © 2001 Wiley-Liss, Inc. INTRODUCTION T-cell prolymphocytic leukemia (T-PLL) is a rare form of malignant proliferation of lymphoid cells with a mature (postthymic) T-cell phenotype. It is typically characterized by a large tumoral mass and an aggressive clinical course with a short sur- vival (Matutes et al., 1991; Garand et al., 1998). Cytogenetic studies of T-PLL reported complex karyotypes with some recurrent chromosomal ab- normalities (Brito-Babapulle et al., 1987; Matutes et al., 1991; Heinonen et al., 1994; Mossafa et al., 1994; Maljaie et al., 1998; Salomon-Nguyen et al., 1998). The Xq28 or the 14q32.1 regions are in- volved in translocations or inversions with the TCRA/D at 14q11. Molecular characterization of these rearrangements led to the identification of the MTCP1, TCL1, and TCL1b genes (Stern et al., 1993; Virgilio et al., 1994; Pekarsky et al., 1999). Unbalanced rearrangements of chromosome 8 have been reported in 40% to 80% of the patients. They are i(8)(q10), t(8;8)(p12;q11), or translocations in- volving 8p and other chromosomal partners, lead- ing to trisomy 8q and/or monosomy 8p (Mossafa et al., 1994; Maljaie et al., 1998). More recently, re- current losses of the 11q21– q23 region have been reported using fluorescence in situ hybridization (FISH) and loss of heterozygozity (LOH) analysis, and biallelic inactivation of the ATM gene was demonstrated in virtually all the sporadic T-PLLs, demonstrating that ATM has a tumor suppressor gene function (Stilgenbauer et al., 1997; Vorecho- vsky et al., 1997; Stoppa-Lyonnet et al., 1998, 2000; Yuille et al., 1998). Deletions of 12p have also been found in T-PLL, using FISH and LOH methods, with a frequency of 43% (Salomon-Nguyen et al., 1998; Hetet et al., 2000). Finally, recurrent dele- tions or translocations of chromosome arms 6q, 13q, 17p, and monosomy 22 have occasionally been re- ported by standard cytogenetics or FISH analyses (Matutes et al., 1991; Mossafa et al., 1994; Rosen- wald et al., 1999). Supported by: l’INSERM, le Comite ´ de Paris de la Ligue Natio- nale Contre le Cancer, and the Ministe ` re de l’Enseignement Su- pe ´ rieur et de la Recherche. *Correspondence to: Jean Soulier, INSERM U509, Institut Curie, 75248 Paris Cedex 5, France. E-mail: jsoulier@chu-stlouis.fr Received 25 September 2000; Accepted 8 December 2000 Published online 30 April 2001 GENES, CHROMOSOMES & CANCER 31:248 –254 (2001) © 2001 Wiley-Liss, Inc.