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

Abstract

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 5 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 de-phosphorylation of ERK, a downstream RAS target which may be critical for mutant RAS-induced cell growth. In addition, PTPRG expression is up-regulated 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.

Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition

“…28,29 Thus, additional cooperating factors must influence survival of these low-level mutated clones during treatment and contribute to Ras pathway-mutated leukemia progression and relapse. 30 Although transgenic models suggest that oncogenic Ras can initiate leukemia and may be a primary event (reviewed in Ward et al 31 ), we show that this is a common secondary genetic event during leukemogenesis that may or may not confer a survival advantage during ALL therapy.…”

Down-regulation of Protein Tyrosine Phosphatase Receptor Gamma (PTPRG) in Chronic Myeloid Leukemia Patients in The State of Qatar is Due to Aberrant DNA Methylation Mechanism

“…PTPRG expression has been shown to be down-regulated by RAS activation, while its up-regulation has been observed in hypo-methylation condition in in childhood acute lymphoblastic leukemia (ALL) [48]. Finally, PTPRG methylation has also been reported in solid cancer [49,50].…”

Receptor-type protein tyrosine phosphatases in cancer

“…Promoter methylation is also an important mechanism for PTPR inactivation in cancer. PTPRG is hypermethylated in multiple cancers including breast cancer [36] , gastric cancer [37] , nasopharyngeal carcinoma [38] , Lynch syndrome CRC [39] , childhood acute lymphoblastic leukemia [40] , and cutaneous T-cell lymphoma [41] . PTPRG expression is negatively correlated with methylation, and when treated with methylation-suppressive agents like 5-aza-2′-deoxycytidine, PTPRG expression can be recovered [37] , [41] .…”

“…PTPRG expression is negatively correlated with methylation, and when treated with methylation-suppressive agents like 5-aza-2′-deoxycytidine, PTPRG expression can be recovered [37] , [41] . A study of childhood acute lymphoblastic leukemia suggested that PTPRG methylation is induced by Ras mutations [40] .…”