ABSTRACT
Pten/Mmac1+/- heterozygous mice exhibited neoplasms in multiple organs including the endometrium, liver, prostate, gastrointestinal tract, thyroid, and thymus. Loss of the wild-type allele was detected in neoplasms of the thymus and liver. Surprisingly, tumors of the gastrointestinal epithelium developed in association with gut lymphoid tissue. Tumors of the endometrium, thyroid, prostate, and liver were not associated with lymphoid tissue and appeared to be highly mitotic. In addition, these mice have nonneoplastic hyperplasia of lymph nodes that was caused by an inherited defect in apoptosis detected in B cells and macrophages. Examination of peripheral lymphoid tissue including lymphoid aggregates associated with polyps revealed that the normal organization of B and T cells was disrupted in heterozygous animals. Taken together, these data suggest that PTEN is a regulator of apoptosis and proliferation that behaves as a "landscaper" tumor suppressor in the gut and a "gatekeeper" tumor suppressor in other organs.
Subject(s)
Genes, Tumor Suppressor , Neoplasms, Experimental/genetics , Phosphoric Monoester Hydrolases/genetics , Tumor Suppressor Proteins , Animals , Animals, Newborn , Crosses, Genetic , Embryonic and Fetal Development , Female , Gene Expression Regulation, Developmental , Genetic Predisposition to Disease , Genotype , Hamartoma Syndrome, Multiple/genetics , Heterozygote , Male , Mice , Mice, Knockout , Neoplasms, Experimental/pathology , PTEN Phosphohydrolase , Phosphoric Monoester Hydrolases/biosynthesis , Phosphoric Monoester Hydrolases/deficiency , Pregnancy , Restriction MappingABSTRACT
15 cases of acute leukemia (AL) displaying a TdT+, HLA-DR+ phenotype were studied; surface immunoglobulins, T cell markers and the common acute lymphoblastic leukaemia (c-ALL) antigen were negative, as were peroxidase and non-specific esterase cytochemical reactions. All cases were extensively investigated by conventional immunofluorescence (IF) and immunoperoxidase (IP), with a panel of monoclonal antibodies (MoAb), using both light and electron microscopy, and for ultrastructural myeloperoxidase (MPO). 8 cases, which were OKB2+, BA1+, B4+, J5- and BA2- by IF, expressed the J5 antigen in IP. These cases were therefore re-classified as ALL with a weak expression of the C-ALL antigen. The other 7 cases showed an OKB2-, BA1-, B4+, BA2+ phenotype at IF and were also positive for 1 or more anti-myeloid MoAb. These features were confirmed by IP study. 4 patients also presented ultrastructural positivity to MPO. These cases were considered as proliferations of early precursor cells capable of expressing both myeloid and lymphoid features. This study, while demonstrating the heterogeneity of TdT+, HLA-DR+ AL, suggests that the cell origin of many cases may be defined by extensive immunotyping at both IF and IP level. The prognostic and therapeutic implications of these findings are discussed, also in view of the poor prognosis often observed in the more undifferentiated cases of AL.
