British Journal of Haematology , 2000, 110, 831±838 T-cell prolymphocytic leukaemia: antigen receptor gene rearrangement and a novel mode of MTCP1 B1 activation P. J. J. C. De Schouwer , M. J. S. Dyer , V. B. Brito-Babapulle , E. Matutes , D. Catovsky and M. R. Yuille Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Sutton, Surrey, UK Received 12 December 1999; accepted for publication 8 May 2000 Summary. T-cell prolymphocytic leukaemia (T-PLL) is a sporadic, mature T-cell disorder in which there is usually an aberrant T-cell receptor alpha (TCRA) rearrangement that activates the TCL1 or MTCP1-B1 oncogenes. As mutations of the Ataxia Telangiectasia (A-T) gene, ATM, are frequent in T-PLL and as ATM seems to act as a tumour suppressor through a mechanism involving V(D)J recombination, we examined V(D)J recombination in T-PLL. Using Southern blotting and the polymerase chain reaction, two of 60 TCRG coding joints were abnormal. In all cases, both TCRD alleles were deleted, IGH was germline, and patterns of TCRB and TCRA rearrangement were normal. However, in a case harbouring t(X;7)(q28;q35), we identified TCRB segment Jb2´7 juxtaposed to MTCP1 exon 1. This is the first time that TCRB has been implicated in MTCP1 B1 activation. The structure of the breakpoint supports a model in which translocation activates a cryptic MTCP1 promoter. This analysis of V(D)J recombination is consistent with it being a variable that is independent of ATM in T-PLL. Keywords: T-PLL, TCRB, MTCP1, TCRG, rearrangement. T-cell prolymphocytic leukaemia (T-PLL) is the most common of the sporadic mature T-cell leukaemias and manifests complex karyotypic changes (Brito-Babapulle et al, 1987; Matutes et al, 1991). The same disease is found in Ataxia Telangiectasia (A-T) at a substantially elevated frequency (Brito-Babapulle & Catovsky, 1991; Taylor et al, 1996). In non-A-T-related T- PLL, rearrangement of the A-T gene, ATM, is frequent and sequence mutations arise in about 50% of cases (Stilgen- bauer et al, 1997; Vorechovsky et al, 1997; Stoppa-Lyonnet et al, 1998; Yuille et al, 1998). This provides evidence that ATM acts as a type of tumour suppressor. A-T is a recessive chromosomal instability syndrome with a pleiotropic phenotype (Lavin & Shiloh, 1996). This phenotype includes elevated risk of T-lymphoid tumours where chromo- some translocations involving the T-cell receptor (TCR) loci occur at high frequency (Kirsch, 1994; Taylor et al, 1996). In T-PLL, one TCRA allele at 14q11 is juxtaposed to either of two oncogenes: the TCL1 locus at 14q32.1 or the MTCP1 locus at Xq28 (Fisch et al, 1993; Stern et al, 1993; Thick et al, 1994; Virgilio et al, 1994,1998; Madani et al, 1996). In metaphases obtained from 51 T-PLL cases seen in this department, 46% harboured inv(14)(q11;q32.1), 26% harboured t(14;14)(q11;q32.1) and 4% harboured t(X;14) (q28;q11). Atm±/±mice always develop thymic lymphomas that have TCR-associated translocations (Barlow et al, 1996; Elson et al, 1996; Xu & Baltimore, 1996). However, this lymphomagenesis is suppressed if V(D)J recombination is blocked, providing evidence that a tumour suppressor function of ATM acts through a mechanism involving V(D)J recombination (Liao & Van Dyke, 1999). By contrast, we have presented a model of tumorigenesis for non-A-T- related T-PLL in which TCL1 or MTCP1 B1 oncogene activation arises from aberrant V(D)J recombination, but this is independent of mutation at ATM (Yuille & Coignet, 1998). In order to investigate V(D)J recombination and its possible relationship to a tumour suppressor function of ATM in T-PLL, we examined a large panel of non-A-T-related T-PLL cases. We report here on rearrangement at TCRB (in chromosome 7q35), TCRA, TCRD (within the TCRA locus), TCRG (in chromosome 7p13), as well as at IGH (in chromosome 14q32.3). This analysis is consistent with V(D)J recombina- tion being a variable that is independent of ATM in T-PLL. We also report a novel translocation breakpoint between TCRB and MTCP1 that provides evidence for activation by translocation of a cryptic MTCP1 B1 promoter. PATIENTS AND METHODS Patient samples. Samples were taken at diagnosis prior to treatment from T-PLL cases seen at or referred to the Royal q 2000 Blackwell Science Ltd 831 Correspondence: M. R. Yuille, Institute of Cancer Research, Academic Department of Haematology and Cytogenetics, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. E-mail: myuille@icr.ac.uk