DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia

Abstract

Aberrant DNA promoter methylation with associated gene silencing is a common epigenetic abnormality in acute lymphoblastic leukaemia (ALL) and is associated with poor survival. We have identified a family of transmembrane tyrosine phosphatase proteins as targets of hypermethylation in ALL and high-grade B cell lymphoma and demonstrated that this abnormal methylation correlates with transcript expression. PTPRG was methylated in 63% of ALL samples, PTPRK in 47%, PTPRM in 64% and PTPRO in 54% of cases, with most ALL samples containing methylation at multiple phosphatase loci. PTPRK promoter methylation was associated with a decreased overall survival in the cohort. Restoration of PTPRK transcript levels in leukaemia cells, where phosphatase transcript was silenced, reduced cell proliferation, inhibited colony formation and increased sensitivity to cytotoxic chemotherapy. These biological changes were associated with a reduction in levels of phosphorylated Erk1/2, Akt, STAT3 and STAT5 suggesting functional phosphatase activity after transcript re-expression. Methylation of the phosphatase promoters was reversible with decitabine and a histone deacetylase inhibitor, suggesting that PTPRK-mediated cell signalling pathways may be targeted with epigenetic therapies in lymphoid malignancy.

Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma

“…45 However, our results showed that PTPRK inactivation by somatic mutations is not a major mechanism in NKTCL. Recently, aberrant hypermethylation of the PTPRK gene promoter was described in 47% of primary acute lymphoblastic leukemia cases, 42 and our results suggest that transcriptional silencing through aberrant promoter hypermethylation exacerbates the consequences of allelic loss of the PTPRK gene in NKTCL.…”

“…22,23 PTPRK has also been linked to the downregulation of other signaling pathways. It was recently reported that Raji cells transduced with PTPRK showed decreased levels of phospho-Erk1/2 (T202/Y204), phospho-Akt (S473), phospho-STAT3 (S727), and phospho-STAT5 (Y694), 42 whereas increased levels of tyrosine-phosphorylated JNK were reported in PTPRK-knockdown prostate cancer cells. 46 Although these studies implied that PTPRK regulates the phosphorylation of these proteins, the authors did not investigate which one of these dephosphorylation of proteins was directly mediated by PTPRK.…”

“…41 A decrease in cell proliferation and colony formation rate was also reported in Raji (Burkitt lymphoma B-cell line) and Jurkat (T-cell leukemia cell line) cells transduced with PTPRK. 42 Further evidence for the role of PTPRK in lymphomagenesis comes from previous studies of primary central nervous system lymphomas (CNSLs) with a 140-kb deletion at 6q22-q23 (which contains the PTPRK gene), as well as the observation that a loss of PTPRK expression is common in CNSLs. 43 Moreover, there is a tendency for a shorter survival time in CNSL patients with tumors that lack PTPRK expression compared with patients whose tumors maintain PTPRK expression.…”

“…42 Traditional chemotherapeutic regimens typically result in overall response rates of only 40% to 50% for newly diagnosed NKTCL patients and are typically ineffective for relapsed cases. 33 A novel protocol, SMILE, was recently developed and has resulted in overall response rates of ; 80%.…”

The Stat3/5 Signaling Biosignature in Hematopoietic Stem/Progenitor Cells Predicts Response and Outcome in Myelodysplastic Syndrome Patients Treated with Azacitidine

“…In both adult and pediatric AML, functional phenotyping of Stat3/5 signaling networks by phospho-protein flow cytometry provides important prognostic information and pathobiologic insights (12,27,37). Yet, despite the reciprocal interactions of DNA methylation with Stat3/5 signaling (19,29,38), the high rate of mutations (39) and aberrant methylation of genes involved in cell signaling (18) in high risk MDS, no current study addresses the Stat3/5 signaling alterations at the single HSPC level in such patients. Only a recent study explored signaling abnormalities in MDS, but it was mainly focused on erythropoietin-induced Stat5 phosphorylation in erythroid progenitors in early disease stages (6).…”