DNA METHYLATION AND DEVELOPMENTAL GENES IN LYMPHOMAGENESIS - MORE QUESTIONS THAN ANSWERS

There is now considerable evidence suggesting that alterations in the DNA methylating machinery play an important role in tumorigenesis and tumour progression. For example, focal hypermethylation and generalise d genomic demethylation are features of many different types of neopla sms. It is thought that tumorigenesis and tumour progression may be ca used by hypermethylation induced mutational events and silencing of ge nes which control cellular proliferation and/or demethylation induced reactivation of genes which may only be required during embryological development. Consequently, we have begun to investigate the role of DN A methylation and developmental genes in malignant lymphoproliferative diseases. Previously, in all cases of non-Hodgkins lymphoma and leuke mia studied, we have shown that the myogenic developmental gene Myf-3 is abnormally hypermethylated. In this review we discuss the possible significance of these findings since in vitro studies suggest that Myf -3 may play an important role in control of the cell cycle and therefo re lymphomagenesis. In vitro and in vivo evidence suggests that PAX ge nes may also have oncogenic potential. The PAX family of developmental genes are involved in cellular differentiation, proliferation and cel l migration. Expression of PAX3 in particular is associated with cellu lar mobility. Our previous studies have indicated that alternate regio nal expression of PAX genes may be controlled by DNA methylation. Ther efore, we have proposed that abnormal methylation profiles of PAX3 may be associated with neoplastic transformation and/or metastatic potent ial. Results thus far reveal that the paired box of PAX3 is abnormally hypermethylated and the homeobox abnormally hypomethylated in lymphom as and leukemias. These new findings are consistent with our postulate and support the idea that inappropriate methylation induced activatio n or inactivation of developmental genes such as Myf-3 and PAX3 play a n important role in lymphomagenesis and disease progression and that i nspection of the methylation status of other developmental genes is wa rranted.