Search

T-cell prolymphocytic leukemia (T-PLL) is consistently associated with inactivation of the ATMgene and chromosomal re-arrangements leading to an overexpression of MTCP1/TCL1 oncoproteins. These alterations are present at the earliest stage of malignant transformation, suggesting that additional events are required for overt malignancy. In this study, we pursued the investigation of the 12p13 deletion, previously shown to occur in approximately half of T-PLLs. We refined the minimal region of deletion by single nucleotide and microsatellite polymorphism allelotyping. We defined a 216-kb region containing the CDKN1Bgene that encodes the cyclin-dependent kinase inhibitory protein p27KIP1. Sequencing this gene in 47 T-PLL patient samples revealed a nonsense mutation in one case without 12p13 deletion. The absence of biallelic inactivation of CDKN1Bfor most patients suggested a haploinsufficiency mechanism for tumor suppression, which was investigated in an animal model of the disease. In a Cdkn1b+/−background, MTCP1transgenics had consistent and multiple emergences of preleukemic clones not observed in control cohorts. The second Cdkn1ballele was maintained and expressed in these preleukemic clones. Altogether, these data strongly implicate CDKN1Bhaploinsufficiency in the pathogenesis of T-PLL.

The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from EμSRα-TEL-JAK2 transgenic mice present an aberrant CD8+ differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4−CD8− double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3ϵ- and pTα-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR–deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCRαβ transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCRαβ expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs.

Human ?d T lymphocytes represent a minor subset of T cells in the peripheral blood, which exhibit a limited diversity and a tissue-restricted repertoire in contrast to their broad specificity. Most postthymic neoplasms that arise from this T-cell subpopulation belong to the hepatosplenic ?d lymphoma entity. Only a few cases of nonhepatosplenic ?d lymphomas have been described in detail previously. This study presents the clinicopathologic features of 11 consecutive cases of nonhepatosplenic ?d lymphoma. All were characterized by mucosal or skin initial involvement: nasal cavity (n?=?3), gastrointestinal tract (n?=?3), skin (n?=?3), lung (n?=?1), larynx (n?=?1). Most patients presented with B symptoms (eight of 11), without peripheral lymphadenopathy and bone marrow involvement. A past history of chronic antigen exposure was noted in six cases, and four patients had features of immune deficiency. On histology, they were classified as pleomorphic tumors. Features of epitheliotropism and angiocentrism was observed in most cases. Tumor cells had a CD2+, CD3+, T-cell receptor (TCR)d-1+, ßF1- phenotype. They were CD5- (9 of 10) and CD4-/CD8- (9 of 10) or CD8+(1 of 10). A clonal ?-chain gene rearrangement was detected in all tested cases (9/9). All cases had an activated cytotoxic T-cell intracellular antigen-1 (TIA-1)+, Granzyme B+ phenotype. Epstein-Barr virus (EBV) sequences were detected in six cases by in situ hybridization (ISH). Despite an aggressive clinical course, complete remission was obtained in three patients, and one of the latter required a peripheral blood stem-cell transplantation. Nonhepatosplenic ?d peripheral T-cell lymphoma can be regarded as a model of activated cytotoxic lymphoma, occurring in mucosae or skin. These appear to be derived from the subpopulation of tissue-restricted ?d lymphocytes, which are involved in the host epithelial surface surveillance. The role of chronic antigen exposure in the pathogenesis of these rare lymphomas can be suggested, in view of the past history observed in at least some patients.

Specific and recurrent chromosomal rearrangements are often observed in the karyotypes of phytohemagglutinin-stimulated lymphocytes. The percentage of cells demonstrating these rearrangements is dramatically increased in the genetic disease ataxia telangiectasia. Inversion of chromosome 7 represents approximately half of the chromosomal rearrangements in this disease. Because the chromosomal locations of the inv(7) breakpoints coincide precisely with those of the T-cell antigen receptor (TCR) β and γ genes, it has been hypothesized that this rearrangement may occur by recombination between those two loci. Here, we present direct evidence that inversion of chromosome 7 in ataxia telangiectasia is generated by site-specific recombination between a TCRγ variable segment and a TCRβ joining segment.

T-cell prolymphocytic leukemia (T-PLL), a rare form of mature T-cell leukemias, and ataxia telangiectasia clonal proliferation, a related condition occurring in patients suffering from ataxia telangiectasia, have been associated to translocations involving the 14q32.1 or Xq28 regions, where are located the TCL1and MTCP1putative oncogenes, respectively. The MTCP1gene is involved in the t(X;14)(q28;q11) translocation associated with these T-cell proliferations. Alternative splicing generates type A and B transcripts that potentially encode two entirely distinct proteins: type A transcripts code for a small mitochondrial protein, p8MTCP1, and type B transcripts, containing an additional open reading frame, may code for a 107 amino-acid protein, p13MTCP1. The recently cloned TCL1gene, also involved in translocations and inversions associated with T-cell proliferations, codes for a 14-kD protein that displays significant homology with p13MTCP1. We have generated rabbit antisera against this putative p13MTCP1protein and screened for expression of p13MTCP1normal lymphoid tissues and 33 cases of immature and mature lymphoid T-cell proliferations, using a sensitive Western blot assay. We also investigated the MTCP1locus configuration by Southern blot analysis. The p13MTCP1protein was detected in the three T-cell proliferations with MTCP1rearrangements because of t(X;14) translocations, but neither in normal resting and activated lymphocytes nor in the other T-cell leukemias. Our data support the hypothesis that p13MTCP1and p14TCL1form a new protein family that plays a key role in the pathogenesis of T-PLL and related conditions.

No constant genetic alteration has yet been unravelled in T-cell acute lymphoblastic leukemia (T-ALL), and, to date, the most frequent alteration, the SIL-TAL1deletion, is found in approximately 20% of cases. Recently, two genes have been identified, the multiple tumor-suppressor gene 1 (MTS1)and multiple tumor-suppressor gene 2 (MTS2], whose products inhibit cell cycle progression. A characterization of the MTSlocus organization allowed to determine the incidence of MTS1and MTS2inactivation in T-ALL. MTS1and MTS2configurations were determined by Southern blotting using 8 probes in 59 patients with T-ALL (40 children and 19 adults). Biallelic MTS1inactivation by deletions and/or rearrangements was observed in 45 cases (76%). Monoallelic alterations were found in 6 cases (10%). The second MTS1allele was studied in the 4 cases with available material. A point mutation was found in 2 cases. The lack of MTS1mRNA expression was observed by Northern blot analysis in a third case. A normal single-strand conformation polymorphism pattern of MTS1exons 1α and 2 was found and MTS1RNA was detected in the fourth case, but a rearrangement occurring 5’ to MTS1exon 1 α deleting MTS1exon 1β was documented. One case presented a complex rearrangement. Germline configuration for MTS1and MTS2was found in only 7 cases. The localization of the 17 breakpoints occurring in the MTS locus were determined. Ten of them (59%) are clustered in a 6-kb region located 5 kb downstream to the newly identified MTS1exon 1β. No rearrangement disrupting MTS2was detected and more rearrangements spared MTS2than MTS1(P< .01). MTS1but not MTS2RNA was detected by Northern blotting in the human thymus. These data strongly suggest that MTS1is the functional target of rearrangements in T-ALL. MTS1inactivation, observed in at least 80% of T-ALL, is the most consistent genetic defect found in this disease to date.

Cytogenetically abnormal T-cell nonmalignant clones are a characteristic feature of ataxia telangiectasia (AT). Here, we study a t(14;14) clone from a patient with AT, and provide a cytological, immunological, and molecular characterization. This cellular population is clonal at the molecular level, but is phenotypically heterogeneous, with CD4+CD8+and CD4-CD8+cells. Although these cells do not divide in the peripheral blood, a majority of them are found in G1phase and express the membrane antigen 4F2, a very early marker of activation. Many similarities are found between this nonmalignant AT clone and T-cell prolymphocytic leukemia at the morphologic, cytogenetic, and immunologic levels, despite the different clinical courses associated with these proliferations. We hypothesize that the t(14;14) translocation is linked to the abnormal morphology and immunophenotype of the AT clone cells, but that this translocation confers only a preactivated state to the cells. A complete malignant transformation would then be due to secondary events. ® 1989 by Grune & Stratton, Inc.

T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature T-cell leukemia associated with chromosomal rearrangements implicatingMTCP1or TCL1genes. These genes encode two homologous proteins, p13MTCP1and p14TCL1, which share no similarity with other known protein. To determine the oncogenic role of MTCP1, mice transgenic for MTCP1under the control of CD2 regulatory regions (CD2-p13 mice) were generated. No abnormality was detected during the first year after birth. A late effect of the transgene was searched for in a cohort of 48 CD2-p13 mice aged 15 to 20 months, issued from 3 independent founders. Lymphoid hemopathies, occurring in the three transgenic lines, were characterized by lymphoid cells with an irregular nucleus, a unique and prominent nucleolus, condensed chromatin, a basophilic cytoplasm devoid of granules, and an immunophenotype of mature T cells. The molecular characterization of Tcrbrearrangements demonstrated the monoclonal origin of these populations. Histopathological analysis of the cohort demonstrated early splenic and hepatic infiltrations, whereas lymphocytosis and medullar infiltrations were found infrequently. The engraftment of these proliferations in H2-matched animals demonstrated their malignant nature. Cumulative incidence of the disease at 20 months was 100%, 50%, and 21% in F3, F4, and F7 lines, respectively, and null in the control group. The level of expression of the transgene, as estimated by Western blotting in the transgenic lines correlated with the tumoral incidence, with the highest expression of p13MTCP1being found in F3 mice. CD2-p13 transgenic mice developed an hemopathy similar to human T-PLL. These data demonstrate that p13MTCP1is an oncoprotein and that CD2-p13 transgenic mice represent the first animal model for mature T-PLL.

T-cell prolymphocytic leukemia (T-PLL) is a rare disease with an aggressive clinical course and a median overall survival of less than three years. Although almost 75% of T-PLL patients are reported to harbor translocations causing the activation of the proto-oncogene TCL1A, T-PLL is genetically heterogenous: most T-PLL patients also have mutations or deletions in the ATMgene and the genes involved in the JAK-STAT pathway are mutated in 76% of cases. There is an urgent need for more rational based therapies, but clinical trials are difficult to perform due to the rareness of the disease. Here, we systematically explored the diversity of drug responses in T-PLL patient samples ex vivousing a drug sensitivity and resistance testing (DSRT) system including 306 oncology drugs (approved or investigational). We also aimed to determine any associations between the genetic aberrations and drug sensitivities in T-PLL patients.