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 TCL1genes. These genes encode two homologous proteins, p13(MTCP1) and p14(TCL1) which share no similarity with other known protein. To d etermine the oncogenic role of MTCP1, mice transgenic for MTCP1 under the control of CD2 regulatory regions (CD2-p13 mice) were generated. N o abnormality was detected during the first year after birth. A late e ffect 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 he mopathies, occurring in the three transgenic lines, were characterized by lymphoid cells with an irregular nucleus, a unique and prominent n ucleolus, condensed chromatin, a basophilic cytoplasm devoid of granul es, and an immunophenotype of mature T cells. The molecular characteri zation of Tcrb rearrangements demonstrated the monoclonal origin of th ese populations. Histopathological analysis of the cohort demonstrated early splenic and hepatic infiltrations, whereas lymphocytosis and me dullar infiltrations were found infrequently. The engraftment of these proliferations in H2-matched animals demonstrated their malignant nat ure. Cumulative incidence of the disease at 20 months was 100%, 50%, a nd 21% in F3, F4, and F7 lines, respectively, and null in the control group. The level of expression of the transgene, as estimated by Weste rn blotting in the transgenic lines correlated with the tumoral incide nce, with the highest expression of p13(MATCP1) being found in F3 mice . CD2-p13 transgenic mice developed an hemopathy similar to human T-PL L. These data demonstrate that p13(MTCP1) is an oncoprotein and that C D2-p13 transgenic mice represent the first animal model for mature T P LL. (C) 1998 by The American Society of Hematology.