We developed two complement-fixing MoAbsHIMand HIM(murine)that were specifically reac-tive with chronic myelogenous leukemia (CML) cells.They were capable of fixing human or rabbit com-plement and suitable for CML cel...We developed two complement-fixing MoAbsHIMand HIM(murine)that were specifically reac-tive with chronic myelogenous leukemia (CML) cells.They were capable of fixing human or rabbit com-plement and suitable for CML cells purging of re-mission marrow from CML patients.HIMreactedwith majority leukemic cells form 7 out of 10 CMLpatients by complement-mediated cytotoxicity(C’MC)assay(positive cells 80%—90%),HIMreacted withmajority CML cells from 4 out of 5 CML by C’MCassay(positive cells 80%—90%).Treatment withHIMor HIMand human C’was capable of lysing97% of K562,U937,HL-60 and CML cells in a 20fold excess of unrelated cells by indirect FITC+EBstain.Using limited dilution culture,incubation withHIMand C’produced 1.5 logs inhibition of growthin K562 cells,and 1.9 logs in U937 cells,and withHIMand C’produced 2.9 logs inhibition in HL-60cells and 3.0 logs in U937 cells.Both MoAbs cocktailwas shown 1.8 logs in K562 cells and 3.2 logs in U937cells.They were no suppression on the growth o展开更多
Background Homoharringtonine （HHT） is effective in treating late stage chronic myelogenous leukaemia （CML）, but little is known about long term maintenance during complete cytogenetic response. Long term efficacy ...Background Homoharringtonine （HHT） is effective in treating late stage chronic myelogenous leukaemia （CML）, but little is known about long term maintenance during complete cytogenetic response. Long term efficacy and toxicity profiles of low dose HHT were evaluated in this study. Methods One hundred and six patients with CML received 1.5 mg/m^2 of HHT alone by continuous daily infusion for seven to nine days every four weeks. Of 79 patients in the control group, 31 were treated with interferon α （IFN-α） and 48 with hydroxycarbamide. For 17 patients who failed to achieve cytogenetic response within 12 months＇ treatment of IFN-α, HHT was administered. Quantitative RT-PCR was used to detect the BCR-ABL mRNA expression in 36 Philadelphia positive CML patients enrolled after 2007. Haematological and cytogenetic responses were evaluated in all patients at the 12th month of follow-up. Long term efficacy was assessed in a follow-up with a median time of 54 months （12 months-98 months）. Results After 12 months of therapy, cytogenetic response rate of the HHT, IFN-α and hydroxycarbamide groups were 39/106, 14/31 and 3/48, and corresponding molecular cytogenetic response rates 6/18, 3/8 and 0. Of the 17 patients who received HHT as salvage treatment, 6 achieved cytogenetic response （3 major）. At the 48 months＇ follow-up, cytogenetic response was maintained in 32/39 patients treated with HHT. Patients who had cytogenetic response in HHT group or treated with IFN-α also showed longer median chronic durations, which were 45 months （12 months-98 months） and 49 months （12 months-92 months） respectively, indicating a longer survival time. Conclusions Low dose HHT alone showed considerable short term and long term efficacy in the treatment of late stage CML. It may also be a good choice for patients who have failed imatinib, IFN-α treatment or haematopoietic stem cell transplantation or cannot afford these treatments.展开更多
BCR/ABL is the causative agent of chronic myelogenous leukemia(CML).Through structure/function analysis,several protein motifs have been determined to be important for the development of leukemogenesis.Tyrosine177 of ...BCR/ABL is the causative agent of chronic myelogenous leukemia(CML).Through structure/function analysis,several protein motifs have been determined to be important for the development of leukemogenesis.Tyrosine177 of BCR is a Grb2 binding site required for BCR/ABL-induced CML in mice.In the current study,we use a mouse bone marrow transduction/transplantation system to demonstrate that addition of oncogenic NRAS(NRASG12D)to a vector containing a BCR/ABL^(Y177F)mutant“rescues”the CML phenotype rapidly and efficiently.To further narrow down the pathways downstream of RAS that are responsible for this rescue effect,we utilize well-characterized RAS effector loop mutants and determine that the RAL pathway is important for rapid induction of CML.Inhibition of this pathway by a dominant negative RAL is capable of delaying disease progression.Results from the present study support the notion of RAL inhibition as a potential therapy for BCR/ABL-induced CML.展开更多
文摘We developed two complement-fixing MoAbsHIMand HIM(murine)that were specifically reac-tive with chronic myelogenous leukemia (CML) cells.They were capable of fixing human or rabbit com-plement and suitable for CML cells purging of re-mission marrow from CML patients.HIMreactedwith majority leukemic cells form 7 out of 10 CMLpatients by complement-mediated cytotoxicity(C’MC)assay(positive cells 80%—90%),HIMreacted withmajority CML cells from 4 out of 5 CML by C’MCassay(positive cells 80%—90%).Treatment withHIMor HIMand human C’was capable of lysing97% of K562,U937,HL-60 and CML cells in a 20fold excess of unrelated cells by indirect FITC+EBstain.Using limited dilution culture,incubation withHIMand C’produced 1.5 logs inhibition of growthin K562 cells,and 1.9 logs in U937 cells,and withHIMand C’produced 2.9 logs inhibition in HL-60cells and 3.0 logs in U937 cells.Both MoAbs cocktailwas shown 1.8 logs in K562 cells and 3.2 logs in U937cells.They were no suppression on the growth o
文摘Background Homoharringtonine （HHT） is effective in treating late stage chronic myelogenous leukaemia （CML）, but little is known about long term maintenance during complete cytogenetic response. Long term efficacy and toxicity profiles of low dose HHT were evaluated in this study. Methods One hundred and six patients with CML received 1.5 mg/m^2 of HHT alone by continuous daily infusion for seven to nine days every four weeks. Of 79 patients in the control group, 31 were treated with interferon α （IFN-α） and 48 with hydroxycarbamide. For 17 patients who failed to achieve cytogenetic response within 12 months＇ treatment of IFN-α, HHT was administered. Quantitative RT-PCR was used to detect the BCR-ABL mRNA expression in 36 Philadelphia positive CML patients enrolled after 2007. Haematological and cytogenetic responses were evaluated in all patients at the 12th month of follow-up. Long term efficacy was assessed in a follow-up with a median time of 54 months （12 months-98 months）. Results After 12 months of therapy, cytogenetic response rate of the HHT, IFN-α and hydroxycarbamide groups were 39/106, 14/31 and 3/48, and corresponding molecular cytogenetic response rates 6/18, 3/8 and 0. Of the 17 patients who received HHT as salvage treatment, 6 achieved cytogenetic response （3 major）. At the 48 months＇ follow-up, cytogenetic response was maintained in 32/39 patients treated with HHT. Patients who had cytogenetic response in HHT group or treated with IFN-α also showed longer median chronic durations, which were 45 months （12 months-98 months） and 49 months （12 months-92 months） respectively, indicating a longer survival time. Conclusions Low dose HHT alone showed considerable short term and long term efficacy in the treatment of late stage CML. It may also be a good choice for patients who have failed imatinib, IFN-α treatment or haematopoietic stem cell transplantation or cannot afford these treatments.
基金supported by the National Natural Science Foundation of China(Grant No.81230055)Shanghai Excellent Science Leader Program(No.12XD1403500)the National Natural Science Foundation of China(Grant No.81230055,to R.R.).
文摘BCR/ABL is the causative agent of chronic myelogenous leukemia(CML).Through structure/function analysis,several protein motifs have been determined to be important for the development of leukemogenesis.Tyrosine177 of BCR is a Grb2 binding site required for BCR/ABL-induced CML in mice.In the current study,we use a mouse bone marrow transduction/transplantation system to demonstrate that addition of oncogenic NRAS(NRASG12D)to a vector containing a BCR/ABL^(Y177F)mutant“rescues”the CML phenotype rapidly and efficiently.To further narrow down the pathways downstream of RAS that are responsible for this rescue effect,we utilize well-characterized RAS effector loop mutants and determine that the RAL pathway is important for rapid induction of CML.Inhibition of this pathway by a dominant negative RAL is capable of delaying disease progression.Results from the present study support the notion of RAL inhibition as a potential therapy for BCR/ABL-induced CML.
