title: Methylation and decreased expression of SHP-1 are related to disease progression in chronic myelogenous leukemia.
abstract: Despite the unprecedented success of tyrosine kinase inhibitors (TKIs) in treating chronic myelogenous leukemia (CML), some patients nevertheless progress to advanced stages of the disease. Thus far, the biological basis leading to CML progression remains poorly understood. SH2-containing tyrosine phosphatase 1 (SHP-1) is reported to bind to p210BCR‑ABL1 and to function as a tumor suppressor. Furthermore, its substrates have been found to be essential for p210BCR-ABL1 leukemogenesis or CML progression. In the present study, we found that SHP-1 mRNA and protein levels were markedly decreased in patients in the accelerated and blastic phases of CML (AP-CML and BP-CML) compared to those in the chronic phase (CP-CML). In vitro, we demonstrated that overexpression of SHP-1 reduced p210BCR-ABL1 protein expression and activity in the K562 CML cell line and negatively regulated the AKT, MAPK, MYC and JAK2/STAT5 signaling pathways. Moreover, using a methylation-specific polymerase chain reaction (MSP) assay, abnormal methylation of the SHP-1 gene promoter region was found both in K562 cells and bone marrow (BM) or peripheral blood (PB) cells from AP-CML and BP-CML patients. In conclusion, our findings suggest that decreased expression levels of SHP-1 caused by aberrant promoter hypermethylation may play a key role in the progression of CML by dysregulating BCR-ABL1, AKT, MAPK, MYC and JAK2/STAT5 signaling.
authors.affiliation: Department of Hematology, The Second Hospital of Hebei Medical University, Key Laboratory of Hematology, Shijiazhuang, Hebei 050000, P.R. China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematology, The Second Hospital of Hebei Medical University, Key Laboratory of Hematology, Shijiazhuang, Hebei 050000, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Hematology, The Second Hospital of Hebei Medical University, Key Laboratory of Hematology, Shijiazhuang, Hebei 050000, P.R. China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Hematology, The Second Hospital of Hebei Medical University, Key Laboratory of Hematology, Shijiazhuang, Hebei 050000, P.R. China.
authors.forename: Jingci
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Hematology, The Second Hospital of Hebei Medical University, Key Laboratory of Hematology, Shijiazhuang, Hebei 050000, P.R. China.
authors.forename: Yintao
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Department of Hematology, The Second Hospital of Hebei Medical University, Key Laboratory of Hematology, Shijiazhuang, Hebei 050000, P.R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Luo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002648:Child; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2 / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D050799:STAT5 Transcription Factor / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C489427:MYC protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C498826:nilotinib