Protein Tyrosine Phosphatase Receptor Type {gamma} Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia.

Posted by rob on October 22, 2010 under Uncategorized | Comments are off for this article

Protein Tyrosine Phosphatase Receptor Type {gamma} Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia.

Cancer Res. 2010 Oct 19;

Authors: Della Peruta M, Martinelli G, Moratti E, Pintani D, Vezzalini M, Mafficini A, Grafone T, Iacobucci I, Soverini S, Murineddu M, Vinante F, Tecchio C, Piras G, Gabbas A, Monne M, Sorio C

Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type ? (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34(+) cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL-dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34(+) cells, and is reexpressed following molecular remission of disease. Reexpression was associated with a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2′-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target. Cancer Res; 70(21); 8896-906. ©2010 AACR.

PMID: 20959494 [PubMed - as supplied by publisher]

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The IFNG (IFN-{gamma}) Genotype Predicts Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia.

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The IFNG (IFN-{gamma}) Genotype Predicts Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia.

Clin Cancer Res. 2010 Oct 19;

Authors: Kim DH, Kong JH, Byeun JY, Jung CW, Xu W, Liu X, Kamel-Reid S, Kim YK, Kim HJ, Lipton JH

PURPOSE: The present study analyzed treatment outcomes of imatinib therapy by interindividual genetic variants in candidate biological pathways of chronic myeloid leukemia (CML) such as apoptosis, angiogenesis, IFN-? signaling pathways, or drug transport/metabolism of imatinib. EXPERIMENTAL DESIGN: Peripheral blood DNAs were genotyped for 79 single nucleotide polymorphism markers involved in the pathways of apoptosis, angiogenesis, myeloid cell growth, xenobiotic metabolism, WT1 signaling, IFN signaling, and others in CML patients who were included in discovery (n = 229, Canada) and validation cohorts (n = 187, Korea). RESULTS: We found several genotypes associated with complete cytogenetic response: IFNG (rs1861494, rs2069705), FASL (rs763110), FAS (rs2234767, rs2234978), VEGFR2 (rs1531289), and WT1 (rs2234590); with major molecular response: IFNG (rs1861494, rs2069705), BIRC5 (rs9904341), FAS (rs2234978), and ABCG2 (rs2231142); with loss of response: IFNG (rs2069705), IFNGR2 (rs9808753), BIRC5 (rs9904341), and ORM (rs3182041); and with treatment failure: IFNG (rs2069705), JAK3 (rs3212713), and ORM (rs3182041). External validation for the above significant genotypes confirmed that the IFNG genotype (rs2069705) was predictive of complete cytogenetic response (hazard ratio, 2.17; P < 0.001) and major molecular response (hazard ratio, 1.96; P = 0.0001) in validation cohorts of Korean ethnicity. CONCLUSIONS: The IFNG genotype was predictive for response to imatinib therapy, suggesting potential involvement of the IFN-? signaling pathway in the mechanism of action of imatinib in CML. Clin Cancer Res; 16(21); 5339-50. ©2010 AACR.

PMID: 20959405 [PubMed - as supplied by publisher]

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