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
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
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.
