Effect of Qinghuang Powder(青黄散) Combined with Bupi Yishen Decoction(补脾益肾方) in Treating Patients with Refractory Cytopenia with Multilineage Dysplasia through Regulating DNA Methylation
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摘要
Objective: To explore the effect of Qinghuang Powder(QHP, 青黄散) combined with Bupi Yishen Decoction(BPYS, 补脾益肾方)on myelodysplastic syndromes(MDS) patients with refractory cytopenia with multilineage dysplasia(RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. Methods: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count(ANC), hemoglobin(Hb), platelets(PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation.Gene Ontology(GO) and Pathway analysis were applied to analyze the methylation data. Results: The overall MDS response rate to QHP was 61.68%(190/360) including hematologic improvement-neutrophil(HI-N) or hematologic improvement-erythroid(HI-E) or hematologic improvement-platelet(HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia(55.88% vs 31.54% or 55.88%vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions. Conclusions: QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement(HI-N, HI-P or HI-E)and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.
Objective: To explore the effect of Qinghuang Powder(QHP, 青黄散) combined with Bupi Yishen Decoction(BPYS, 补脾益肾方)on myelodysplastic syndromes(MDS) patients with refractory cytopenia with multilineage dysplasia(RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. Methods: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count(ANC), hemoglobin(Hb), platelets(PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation.Gene Ontology(GO) and Pathway analysis were applied to analyze the methylation data. Results: The overall MDS response rate to QHP was 61.68%(190/360) including hematologic improvement-neutrophil(HI-N) or hematologic improvement-erythroid(HI-E) or hematologic improvement-platelet(HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia(55.88% vs 31.54% or 55.88%vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions. Conclusions: QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement(HI-N, HI-P or HI-E)and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.
Objective: To explore the effect of Qinghuang Powder(QHP, 青黄散) combined with Bupi Yishen Decoction(BPYS, 补脾益肾方)on myelodysplastic syndromes(MDS) patients with refractory cytopenia with multilineage dysplasia(RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula. Methods: All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count(ANC), hemoglobin(Hb), platelets(PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation.Gene Ontology(GO) and Pathway analysis were applied to analyze the methylation data. Results: The overall MDS response rate to QHP was 61.68%(190/360) including hematologic improvement-neutrophil(HI-N) or hematologic improvement-erythroid(HI-E) or hematologic improvement-platelet(HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia(55.88% vs 31.54% or 55.88%vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions. Conclusions: QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement(HI-N, HI-P or HI-E)and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.
引文
1.Tefferi A,Vardiman JW.Myelodysplastic syndromes.NEngl J Med 2009;38:1872-188.
2.Vardiman JW,Harris NL,Brunning RD.WHO classification of tumors of haematopoietic and lymphoid tissues.Blood2002;100:2292-302.
3.Cutler CS,Lee SJ,Greenberg P,Deeg HJ,Pérez WS,Anasetti C,et al.A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes:delayed transplantation for low-risk myelodysplasia is associated with improved outcome.Blood 2004;104:579-585.
4.Anonymous,ed.The Inner Canon of Emperor Huang.Beijing:Chinese Medical Ancient Books Publishing House;2003.
5.Zhang ZJ,ed.Theory of typhoid miscellaneous disease.Beijing:Chinese Medical Ancient Books Publishing House;2008.
6.Xu S,Ma R,Hu XM,Xu YG,Yang XH,Wang HZ,et al.Clinical observation of the treatment of myelodysplastic syndrome mainly with qinghuang powder.Chin J Integr Med 2011;17:834-883.
7.Itzykson R,Fenaux P.Epigenetics of myelodysplastic syndromes.Leukemia 2014;28:497-506.
8.Piekarz RL,Bates SE.Epigenetic modifiers:basic understanding and clinical development.Clin Cancer Res2009;15:3918-3926.
9.Yamazaki J,Issa JP.Epigenetic aspects of MDS and its molecular targeted therapy.Int J Hematol 2013;97:175-182.
10.Issa JP,Kantarjian HM.Targeting DNA methylation.Clin Cancer Res 2009;15:3938-3946.
11.Shuzhen S,Ma R,Hu XM,Yang XH,Xu YG,Hongzhi W,et al.Karyotype and DNA-methylation responses in myelodysplastic syndromes following treatment with traditional Chinese formula containing arsenic.Evid Based Complement Altern Med 2012;5:265-266.
12.Vardiman JW,Thiele J,Arber DA,Brunning RD,Borowitz MJ,Porwit A,et al,The 2008 revision of the World Health Organization(WHO)classification of myeloid neoplasms and acute leukemia:rationale and important changes,Blood 2009;114:937-951.
13.Tefferi A,Barosi G,Mesa RA,Cervantes F,Deeg HJ,Reilly JT,et al.International Working Group(IWG)consensus criteria for treatment response in myelofibrosis with myeloid metaplasia:On behalf of the IWG for myelo fibrosis research and treatment(IWGMRT).Blood 2006;108:1497-1503.
14.Cheson BD,Bennett JM,Kantarjian H,Pinto A,Schiffer CA,Nimer SD,et al.Report of an international working group to standardize response criteria for myelodysplastic syndromes.Blood 2000;96:3671-3674.
15.Berardini TZ.The Gene Ontology in 2010:extensions and refinements.Nucleic Acids Res 2009;38:331-335.
16.Ashburner M,Ball CA,Blake JA,Botstein D,Butler H,Cherry JM,et al.Gene ontology:tool for the unification of biology.Nature Genetics 2000;25:25-29.
17.Aoki-Kinoshita KF,Kanehisa M.Gene annotation and pathway mapping in KEGG.Methods Mol Biol 2007;396:71-91.
18.Kanehisa M.The KEGG database.Novartis Found Symp2002;247:91-103.
19.Greenberg P,Cox C,Le Beau MM,Fenaux P,Morel P,Sanz G,et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood 1997;89:2079-2088.
20.Cheson BD,Bennett JM,Kantarjian H,Pinto A,Schiffer CA,Nimer SD,et al.Report of an international working group to standardize response criteria for myelodysplastic syndromes.Blood 2000;96:3671-3674.
21.Issa JP.The myelodysplastic syndrome as a prototypical epigenetic disease.Blood 2013;121:3811-3817.
22.Jiang Y,Dunbar A,Gondek LP,Mohan S,Rataul M,O'Keefe C,et al.Aberrant DNA methylation is a dominant mechanism in MDS progression to AML.Blood 2009;113:1315-1325.
23.Karasawa T,Yokokura H,Kitajewski J,Lombroso PJ.Frizzled-9 is activated by Wnt-2 and functions in Wnt/betacatenin signaling.J Biol Chem 2002;277:37479-37486.
24.Peng H,Wen J,Zhang L,Li H,Chang CC,Zu Y,et al.Asystematic modeling study on the pathogenic role of p38MAPK activation in myelodysplastic syndromes.Mol Bio Syst 2012;8:1366-1374.
2.Vardiman JW,Harris NL,Brunning RD.WHO classification of tumors of haematopoietic and lymphoid tissues.Blood2002;100:2292-302.
3.Cutler CS,Lee SJ,Greenberg P,Deeg HJ,Pérez WS,Anasetti C,et al.A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes:delayed transplantation for low-risk myelodysplasia is associated with improved outcome.Blood 2004;104:579-585.
4.Anonymous,ed.The Inner Canon of Emperor Huang.Beijing:Chinese Medical Ancient Books Publishing House;2003.
5.Zhang ZJ,ed.Theory of typhoid miscellaneous disease.Beijing:Chinese Medical Ancient Books Publishing House;2008.
6.Xu S,Ma R,Hu XM,Xu YG,Yang XH,Wang HZ,et al.Clinical observation of the treatment of myelodysplastic syndrome mainly with qinghuang powder.Chin J Integr Med 2011;17:834-883.
7.Itzykson R,Fenaux P.Epigenetics of myelodysplastic syndromes.Leukemia 2014;28:497-506.
8.Piekarz RL,Bates SE.Epigenetic modifiers:basic understanding and clinical development.Clin Cancer Res2009;15:3918-3926.
9.Yamazaki J,Issa JP.Epigenetic aspects of MDS and its molecular targeted therapy.Int J Hematol 2013;97:175-182.
10.Issa JP,Kantarjian HM.Targeting DNA methylation.Clin Cancer Res 2009;15:3938-3946.
11.Shuzhen S,Ma R,Hu XM,Yang XH,Xu YG,Hongzhi W,et al.Karyotype and DNA-methylation responses in myelodysplastic syndromes following treatment with traditional Chinese formula containing arsenic.Evid Based Complement Altern Med 2012;5:265-266.
12.Vardiman JW,Thiele J,Arber DA,Brunning RD,Borowitz MJ,Porwit A,et al,The 2008 revision of the World Health Organization(WHO)classification of myeloid neoplasms and acute leukemia:rationale and important changes,Blood 2009;114:937-951.
13.Tefferi A,Barosi G,Mesa RA,Cervantes F,Deeg HJ,Reilly JT,et al.International Working Group(IWG)consensus criteria for treatment response in myelofibrosis with myeloid metaplasia:On behalf of the IWG for myelo fibrosis research and treatment(IWGMRT).Blood 2006;108:1497-1503.
14.Cheson BD,Bennett JM,Kantarjian H,Pinto A,Schiffer CA,Nimer SD,et al.Report of an international working group to standardize response criteria for myelodysplastic syndromes.Blood 2000;96:3671-3674.
15.Berardini TZ.The Gene Ontology in 2010:extensions and refinements.Nucleic Acids Res 2009;38:331-335.
16.Ashburner M,Ball CA,Blake JA,Botstein D,Butler H,Cherry JM,et al.Gene ontology:tool for the unification of biology.Nature Genetics 2000;25:25-29.
17.Aoki-Kinoshita KF,Kanehisa M.Gene annotation and pathway mapping in KEGG.Methods Mol Biol 2007;396:71-91.
18.Kanehisa M.The KEGG database.Novartis Found Symp2002;247:91-103.
19.Greenberg P,Cox C,Le Beau MM,Fenaux P,Morel P,Sanz G,et al.International scoring system for evaluating prognosis in myelodysplastic syndromes.Blood 1997;89:2079-2088.
20.Cheson BD,Bennett JM,Kantarjian H,Pinto A,Schiffer CA,Nimer SD,et al.Report of an international working group to standardize response criteria for myelodysplastic syndromes.Blood 2000;96:3671-3674.
21.Issa JP.The myelodysplastic syndrome as a prototypical epigenetic disease.Blood 2013;121:3811-3817.
22.Jiang Y,Dunbar A,Gondek LP,Mohan S,Rataul M,O'Keefe C,et al.Aberrant DNA methylation is a dominant mechanism in MDS progression to AML.Blood 2009;113:1315-1325.
23.Karasawa T,Yokokura H,Kitajewski J,Lombroso PJ.Frizzled-9 is activated by Wnt-2 and functions in Wnt/betacatenin signaling.J Biol Chem 2002;277:37479-37486.
24.Peng H,Wen J,Zhang L,Li H,Chang CC,Zu Y,et al.Asystematic modeling study on the pathogenic role of p38MAPK activation in myelodysplastic syndromes.Mol Bio Syst 2012;8:1366-1374.
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