PTPRG inhibition by DNA methylation and cooperation with RAS gene activation in childhood acute lymphoblastic leukemia.
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.
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
Jianqiao
J
Xiao
Seung-Tae
ST
Lee
Yuanyuan
Y
Xiao
Xiaomei
X
Ma
E Andres
EA
Houseman
Ling-I
LI
Hsu
Ritu
R
Roy
Margaret
M
Wrensch
Adam J
AJ
de Smith
Anand
A
Chokkalingam
Patricia
P
Buffler
John K
JK
Wiencke
Joseph L
JL
Wiemels
D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D010766:Phosphorylation / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C101743:RREB1 protein, human; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D018631:ras Proteins
DNA methylation; PTPRG; RAS; childhood acute lymphoblastic leukemia