A complex pattern of recurrent chromosomal losses and gains in T‐cell prolymphocytic leukemia

Abstract

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 abnormalities 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.

Combined single nucleotide polymorphism-based genomic mapping and global gene expression profiling identifies novel chromosomal imbalances, mechanisms and candidate genes important in the pathogenesis of T-cell prolymphocytic leukemia with inv(14)(q11q32)

“…A loss of genomic material is indicated by an amplitude to the left and colored in red, a gain of genomic material is marked by an amplitude to the right and green color. As per convention, 3 chromosomal regions that were involved in more than 20% of the cases analyzed were referred to as recurrent.…”

“…[1][2][3] Most T-PLLs exhibit a mature post-thymic CD2 þ , CD3 þ , CD7 þ , CD4 þ , CD8À immunophenotypes, but CD4 þ , CD8 þ and CD4À, CD8 þ cases are also commonly seen. 1,2 The disease follows an aggressive clinical course in most patients with median survival times ranging from 7 to 30 months.…”

“…1,2,4,5 The genetic hallmark of T-PLL is the inversion inv(14)(q11q32) or its variant, the translocation t(14;14)(q11;q32), which are present in up to 80% of the cases. 1,3,6 These rearrangements juxtapose enhancer elements of the TCRAD locus in 14q11 next to oncogenes located within the TCL1 locus in 14q32, whose expression is then deregulated. [7][8][9] Besides the inv (14), which is regarded as the primary oncogenic event in T-PLL, 7-10 the tumor cells usually harbor a high load of additional chromosomal aberrations.…”

“…[7][8][9] Besides the inv (14), which is regarded as the primary oncogenic event in T-PLL, 7-10 the tumor cells usually harbor a high load of additional chromosomal aberrations. 3,6 These secondary chromosomal aberrations include overrepresentations of 8q and deletions of 8p, frequently due to formation of an isochromosome iso(8q), 3,6 as well as losses on chromosome 11, 11,12 and with lower frequency involving other chromosomal regions like 22q and 6q. 3 Although this pattern of secondary changes in inv (14)/t(14;14)-positive T-PLL is highly conserved and characteristic of T-PLL, 3 the target genes of the recurrent secondary aberrations in this disease are largely unknown, except ATM, which is supposed to be the tumor suppressor gene in the commonly deleted region in 11q22B23.…”

“…3,6 These secondary chromosomal aberrations include overrepresentations of 8q and deletions of 8p, frequently due to formation of an isochromosome iso(8q), 3,6 as well as losses on chromosome 11, 11,12 and with lower frequency involving other chromosomal regions like 22q and 6q. 3 Although this pattern of secondary changes in inv (14)/t(14;14)-positive T-PLL is highly conserved and characteristic of T-PLL, 3 the target genes of the recurrent secondary aberrations in this disease are largely unknown, except ATM, which is supposed to be the tumor suppressor gene in the commonly deleted region in 11q22B23. 11,12 In various subtypes of leukemias and lymphomas, array-based transcriptional profiling recently identified characteristic gene expression signatures.…”