Study On Pathogenesis And Treatment Of Bone Marrow And Lymphoproliferative Tumor

Part 1 The potential role of targeting the SOCS1-regulated JAK2-STAT5 signaling pathway by mi R-155 in the development of primary myelofibrosisBackground: Sustained activation of the Janus kinase(JAK)-signal transducer and activator of transcription(STAT)signaling pathway is a common etiological event in a variety of hematological tumors,especially myeloproliferative neoplasms(MPNs).However,the regulatory mechanism has not been fully elucidated.Numerous studies have demonstrated that micro RNA-155(mi R-155)is highly expressed in many tumors and is closely related to tumor development and progression.Objective: The purpose of the present study was to investigate whether mi R-155 participated in the pathogenesis of primary myelofibrosis(PMF)through regulation of the JAK2-STAT5 signaling pathway.Methods: Real-time polymerase chain reaction(PCR)was performed to examine micro RNA and the suppressor of cytokine signaling 1(SOCS1)gene expression.A retrovirus was used as a mi R-155 overexpression vector.The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay was performed to quantify the cell survival rate.Western blotting was performed to analyze the expression of SOCS1 and its downstream signaling molecules JAK2/STAT5.The luciferase reporter gene assay was employed to verify the target effect of mi R-155 on SOCS1.Results: In the present study,compared to healthy individuals,the mi R-155 expression level was significantly increased and the SOCS1 m RNA and protein expression levels were markedly reduced in bone marrow mononuclear cells collected from PMF patients.Using Ba F3 as a cell model,we discovered that mi R-155 overexpression enhanced the sensitivity of the cells to interleukin-3(IL-3)by upregulating JAK2-STAT5 signaling.Further experiments demonstrated that mi R-155 affected the JAK2-STAT5 signaling pathway by regulating the expression of its target gene SOCS1 to exert the biological effects described above.Conclusion: mi R-155 affects JAK2/STAT5 signaling by regulating the expression of its target gene SOCS1,thereby exerting a regulatory effect on the sensitivity of Ba F3 cells to IL-3.The above results provide a new perspective for the pathogenic mechanisms of PMF.Part 2 Once-weekly 1.6mg/m2 bortezomib BCD regimen in elderly patients with newly diagnosed multiple myeloma who are unfit for standard dose chemotherapyBackground: Bortezomib has shown anti-myeloma effects in combination with alkylating agents,but clinical benefits can be limited by neurotoxicity.There is less information on the efficacy and tolerability of once-weekly 1.6mg/m~2 bortezomib BCD regimen in elderly patients with newly diagnosed MM who are unfit for standard dose chemotherapy Objective: Here,we report our experience of weekly 1.6mg/m~2 intravenous bortezomib in this group of patients,access the efficacy and safety of this program?Methods: Between March 2010 and February 2015,we treated 34 newly diagnosed elderly patients with the combination of bortezomib 1.6 mg/m~2 intravenously on days 1 and 8;cyclophosphamide 200mg/m~2 intravenously on days 1–4;dexamethasone 20 mg intravenously on days 1-4,and 8-11.Results: Among the 34 patients,14(41%)responded with CR,6(18%)with VGPR and 10(29%)with PR.The ORRs were 88%.After 2 cycles of treatments,the survival of patients who attained a response of VGPR or CR was significantly longer than those with PR or resistance to BCD,for both progression-free survival(PFS)(21.4 vs.10.6 mo,p=0.002)and overall survival(OS)(23.0 vs.16.8 mo,p=0.043).The 2-year PFS and OS were 26.5% and 64.7% respectively in these elderly MM patients in our study.Grade 1/2 neuropathy was observed in 20% of the cycles while grade 3/4 neuropathy was not observed.No patients withdrew due to neuropathy or other side effects.Conclusion: Once-weekly bortezomib at 1.6mg/m2 BCD regimen is both effective and safe in elderly patients with newly diagnosed MM who are unfit for standard dose chemotherapy.Part 3 Retrospective study of Pegaspargase,Gemicitabine,oxaliplatin and dexamethasone(Peg-Gem OD)as a first-line therapy for advanced-stage extranodal NK/T cell lymphomaBackground: The prognosis of advanced-stage extranodal NK/T cell lymphoma(ENKTL)is extremely poor because of its very aggressive clinical course and unsatisfactory response to conventional combination chemotherapy.Systemic chemotherapy containing drugs unaffected by multidrug resistance pathway are currently recommended for patients with advanced-stage ENKTL.Objective: This study was conducted to retrospectively investigate the efficacy and safety of pegaspargase,gemicitabine,oxaliplatin and dexamethasone(Peg-Gem OD)combination chemotherapy as a first-line therapy for advanced-stage ENKTL.Methods: Clinical prognostic factors from these patients were also collected and analyzed.A cohort of 18 patients with newly diagnosed stage III/IV ENKTL who received Peg-Gem OD regimen as a first-line treatment was retrospectively identified from January 2011 to December 2014.Results: All patients were subjected to 3 to 6 cycles of Peg-Gem OD chemotherapy.After 3 cycles of therapy,the overall response rate(ORR)was 67%(12/18)with a complete response(CR)rate of 28%(5/18)and a partial response(PR)rate of 39%(7/18).The median follow-up period was 18 months(range 3~24 months).The median overall survival(OS)and progression-free survival(PFS)time were 10 and 8.5 months respectively.For those responders(CR+PR),the median OS and PFS time were significantly better than those of non-responders(median OS,15 months vs.10 months;P=0.001 and median PFS,15 months vs.7 months;P=0.001).Furthermore,patients with low plasma EBV-DNA levels after induction chemotherapy had a remarkably longer OS and PFS time(median OS,18 months and median PFS,18 months).The toxicity of Peg-Gem OD regimen was acceptable.Conclusion: The Peg-Gem OD regimen is highly effective and tolerable first-line chemotherapy for newly diagnosed advanced-stage ENKTL and is worth further study in prospective trial.