[Transgenic mice expressing MTCP1: an animal model for T-cell prolymphocytic leukemia]. / Etude des souris transgéniques exprimant p13(MTCP1): un modèle animal de la leucémie prolymphocytaire T.

T-prolymphocytic leukemia (T-PLL) is a rare form of mature T-cell leukemia associated with chromosomal rearrangements of band 14q11, containing the gene TCRA/D, and bands 14q32.1 and Xq28, where the TCL1 and MTCP1 putative oncogenes have been identified. These genes encode two homologous proteins, p14(TCL1) and p13(MTCP1) respectively, which share no similarity with other known proteins. To determine the oncogenic role of MTCP1, transgenic mice with an expression of MTCP1 targetted to the T-cells were generated. A lymphoïd malignancy similar to Human T-PLL occurred in to independent transgenic lines with a high level of expression of the transgene. The cumulative incidence of the disease at 20 months was 100% and 50% respectively, and null in the control group. The oncogenic role of MTCP1 is demonstrated, and the p13(MTCP1) and p14(TCL1) proteins form a new oncoprotein family. The long latency period before emergence of tumors suggests that activation of MTCP1 is not sufficient to generate the malignant transformation. The secondary genetic events implicated in tumoral progression remain to be elucidated, in order to reconstruct the molecular history of the disease.

Transgenic mice for MTCP1 develop T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare form of mature T-cell leukemia associated with chromosomal rearrangements implicating MTCP1 or TCL1 genes. These genes encode two homologous proteins, p13(MTCP1) and p14(TCL1), which share no similarity with other known protein. To determine the oncogenic role of MTCP1, mice transgenic for MTCP1 under 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 Tcrb rearrangements 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 p13(MTCP1) being found in F3 mice. CD2-p13 transgenic mice developed an hemopathy similar to human T-PLL. These data demonstrate that p13(MTCP1) is an oncoprotein and that CD2-p13 transgenic mice represent the first animal model for mature T-PLL.

Early onset of immunoglobulin heavy chain gene rearrangements in normal human bone marrow CD34+ cells.

To characterize early B-cell precursors in humans, we correlated immunoglobulin heavy chain (IgH) gene rearrangement status with the CD34, CD19, and CD10 cell surface markers. Highly purified adult bone marrow (BM) cell fractions were obtained by two successive rounds of flow cytometric cell sorting, and IgH rearrangements were analyzed by polymerase chain reaction (PCR) amplification. Complete VDJH rearrangements were observed in the CD34+ CD19+ fraction, but not in the more immature CD34+ CD19- fraction. About one quarter of these rearrangements had an open reading frame, thus potentially permitting the synthesis of a mu chain. Partial DJH rearrangements were detected in both CD34+ CD19+ and CD34+ CD19- subsets, although they were less abundant in the latter. When triple labeling was used to better characterize the CD34+ CD19- population, DJH rearrangements were found to be present in the CD34(+) CD10+ CD19- fraction, but not in the more primitive CD34+ CD10- CD19-. These results indicate that IgH gene rearrangements occur in CD34+ BM cells and that they initiate in immature progenitors expressing the CD10, but not yet the CD19 surface antigen. Finally, the presence of IgH gene rearrangements in CD34+ BM cells provides a useful marker of clonality to evaluate the possible involvement of these cells in various B-cell lymphoid malignancies.

Alternative origin of p13MTCP1-encoding transcripts in mature T-cell proliferations with t(X;14) translocations.

The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with T-cell prolymphocytic leukemia and related conditions. This gene is unusual in that it codes for two distinct proteins: a small mitochondrial protein, p8MTCP1, and a putative oncogenic protein, p13MTCP1. Scarcity of material from t(X;14)-associated proliferations and very low levels of mRNA expression have so far prevented a thorough description of p13MTCP1-encoding transcripts. Here, we characterize two additional t(X;14) bearing leukemias allowing this analysis. In one case, with a breakpoint located 5' to the MTCP1 gene, the level of transcription of previously described p13MTCP1-encoding transcripts is enhanced. In the second case, with a breakpoint within the MTCP1 intron I, an alternative transcription initiation site is demonstrated in the tumor cells at 229 bp upstream to exon II. The identification of this internal promoter, together with the similarity between TCL1 and MTCP1 genomic structures, allow us to propose a model in which the duplication of an ancestral gene was followed by the insertion of one copy within the intron of a p8-encoding gene, accounting for the unusual feature of the MTCP1 gene.

[Further comments on changes in hepatic function after interposition meso-caval shunt (author's transl)]. / Ulteriori rilievi sulle modificazioni della funzione epatica dopo shunt mesenterico-cava

Further to a previous paper, the Authors followed up ten cirrhotic patients who had all undergone meso-caval shunt with Dacron prosthesis, for ascites or haemorrhage, Functional and anzymatic investigations were carried on over periods up to 10 months. No constant changes in hepatic function parameters were found during the post-operative period, compared to those before surgery. This observation suggests that these investigations might be more useful in defining liver disease than in practical assessment of transient, post-operative liver failure.

[Present position of non-shunt surgery for bleeding oesophageal varices (author's transl)]. / Posizione attuale della chirurgia non derivativa nel trattamento delle emorragie da varici esofagee

This is a critical retrospective study of a homogeneous group of 24 patients with hepatic cirrhosis and portal hypertension who underwent emergency surgery for bleeding oesophageal varices. The adopted procedure was the porta-azygos disconnection, according to Torres-Degni, with or without splenectomy. The criterion derived from the need to stop bleeding, from contraindications to a portal-systemic shunt, or from other situations which are illustrated. The difficulty of selecting in these cases the appropriate surgery and the high operative death rate (46%) is commented. In survivors, the long-term outcome depends on the progress of the underlying liver disease.