PTPRG inhibition by DNA methylation and cooperation with RAS gene activation in childhood acute lymphoblastic leukemia

摘要

While the cytogenetic and genetic characteristics of childhood acute lymphoblastic leukemias (ALL) are well studied, less clearly understood are the contributing epigenetic mechanisms that influence the leukemia phenotype. Our previous studies and others identified gene mutation (RAS) and DNA methylation (FHIT) to be associated with the most common cytogenetic subgroup of childhood ALL, high hyperdiploidy (having five more chromosomes). We screened DNA methylation profiles, using a genome-wide high-dimension platform of 166 childhood ALLs and 6 normal pre-B cell samples and observed a strong association of DNA methylation status at the PTPRG locus in human samples with levels of PTPRG gene expression as well as with RAS gene mutation status. In the 293 cell line, we found that PTPRG expression induces dephosphorylation of ERK, a downstream RAS target that may be critical for mutant RAS-induced cell growth. In addition, PTPRG expression is upregulated by RAS activation under DNA hypomethylating conditions. An element within the PTPRG promoter is bound by the RAS-responsive transcription factor RREB1, also under hypomethylating conditions. In conclusion, we provide evidence that DNA methylation of the PTPRG gene is a complementary event in oncogenesis induced by RAS mutations. Evidence for additional roles for PTPR family member genes is also suggested. This provides a potential therapeutic target for RAS-related leukemias as well as insight into childhood ALL etiology and pathophysiology. What's New? The association of DNA methylation with reduced expression of the tumor suppressor gene FHIT in childhood acute lymphoblastic leukemia (ALL) has raised interest in the exploration of epigenetic mechanisms that contribute to the leukemia phenotype. This manuscript describes a strong association between DNA methylation status of PTPRG, a protein phosphatase, and RAS mutation in childhood ALL. Experiments to determine PTPRG function show that PTPRG protein suppresses ERK phosphorylation by mutant RAS. PTPRG as a tumor suppressor in RAS-activated tumors represents a novel target for leukemia therapy and links an epigenetic modification with a well-known genetic mutation.