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Alternative splicing of transcripts from many cancer-associated genes is believed to play a major role in carcinogenesis as well as in tumor progression. Alternative splicing of one such gene, the neural cell adhesion molecule CD56 (NCAM), impacts the progression, inadequate therapeutic response, and reduced total survival of patients who suffer from numerous malignant neoplasms. Although previous investigations have determined that CD56 exists in three major isoforms (CD56(120kD), CD56(140kD), and CD56(180kD)) with individual structural and functional properties, neither the expression profiles nor the functional relevance of these isoforms in malignant tumors have been consistently investigated. Using new quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) strategies and novel CD56 isoform-specific antibodies, CD56(140kD) was shown to be exclusively expressed in a number of highly malignant CD56(+) neoplasms and was associated with the progression of CD56(+) precursor lesions of unclear malignant potential. Moreover, only CD56(140kD) induced antiapoptotic/proliferative pathways and specifically phosphorylated calcium-dependent kinases that are relevant for tumorigenesis. We conclude, therefore, that the specific detection of CD56 isoforms will help to elucidate their individual functions in the pathogenesis and progression of malignant neoplasms and may have a positive impact on the development of CD56-based immunotherapeutic strategies.

Defects in the mismatch repair system (MMR) underlie hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and also a significant number of sporadic colorectal cancers. Mice carrying a null allele for the MMR gene Mlh1 are preferentially prone to the development of lymphomas of B- and T-cell origin and to a lesser extent gastrointestinal tumors. Consistent with these findings in mice, MMR defects have also been observed in sporadic and hereditary hematological malignancies. To study the role of MLH1 for lymphomagenesis in more detail, we generated a new mouse model carrying a conditional Mlh1 allele (Mlh1(flox/flox)). Mating of these mice with EIIa-Cre recombinase transgenic mice allowed the constitutive inactivation of MLH1, and the resulting Mlh1(Δex4/Δex4) mouse line displays complete MMR deficiency and a cancer predisposition phenotype similar to Mlh1−/− mice. For T-cell specific MMR inactivation we combined the Mlh1(flox/flox) allele with the Lck-Cre transgene. In the resulting Mlh1(TΔex4/TΔex4) mice, MLH1 inactivation is limited to DP/SP thymocytes and naive peripheral T-cells. The development of T-cell lymphomas in Mlh1(TΔex4/TΔex4) mice is significantly reduced compared to Mlh1−/− mice, implying that MMR functions either at very early stages during T-cell development or even earlier in lymphoid precursor cells to suppress lymphomagenesis.