Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients ha...Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression,but little is known about the mechanism.A key transcription factor in hematopoiesis,MYB,has been reported to increase abnormally in several types of aggressive blood disorders including CML.Methods:This study used a zebrafish model to explore the relationship between BCR/ABL1 and c-myb in CML progression.A CML zebrafish model was crossed with a c-myb hyperactivity transgenic line.Results:It was found that both exogenous BCR/ABL1 and c-myb could up-regulate the expression of neutrophil-related genes.More seriously,neutrophil accumulation was observed when BCR/ABL1 was combined with c-myb overexpression.Further studies showed that c-myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c-myb dependent.Taking advantage of this inheritable in vivo model,it was shown that a combination of imatinib and flavopiridol,a cyclin-dependent kinase inhibitor targeting MYB,could more effectively alleviate the aggressive phenotype of the double transgene line.Conclusion:In summary,this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression.The model used in the study could be helpful in high-throughput drug screening in CML transformation.展开更多
This study aims to gain insight into the DNA-specific recognition mechanism of c-Myb transcription factor during the regulation of cell early differentiation and proliferation.Therefore,we chose the chicken myeloid ge...This study aims to gain insight into the DNA-specific recognition mechanism of c-Myb transcription factor during the regulation of cell early differentiation and proliferation.Therefore,we chose the chicken myeloid gene,mitochondrial import protein 1(mim-1),as a target to study the binding specificity between potential dual-Myb-binding sites.The c-Myb-binding site in mim-1 is a pseudo-palindromic sequence AACGGTT,which contains two AACNG consensuses.Simulation studies in different biological scenarios revealed that c-Myb binding with mim-1 in the forward strand(complex F)is more stable than that in the reverse strand(complex R).The principal component analysis(PCA)dynamics trajectory analyses suggested an opening motion of the recognition helices of R2 and R3(R2R3),resulting in the dissociation of DNA from c-Myb in complex R at 330 K,triggered by the reduced electrostatic potential on the surface of R2R3.Furthermore,the DNA confirmation and hydrogen-bond interaction analyses indicated that the major groove width of DNA increased in complex R,which affected on the hydrogenbond formation ability between R2R3 and DNA,and directly resulted in the dissociation of DNA from R2R3.The steered molecular dynamics(SMD)simulation studies also suggested that the electrostatic potential,major groove width,and hydrogen bonds made major contribution to the DNA-specific recognition.In vitro trials confirmed the simulation results that c-Myb specifically bound to mim-1 in the forward strand.This study indicates that the three-dimensional(3D)structure features play an important role in the DNA-specific recognition mechanism by c-Myb besides the AACNG consensuses,which is beneficial to understanding the cell early differentiation and proliferation regulated by c-Myb,as well as the prediction of novel c-Myb-binding motifs in tumorigenesis.展开更多
基金National Key R&D Program of ChinaGrant/Award Number:2018YFA0801000+5 种基金National Natural Science Foundation of ChinaGrant/Award Number:32170830Natural Science Foundation of Guangdong ProvinceChinaGrant/Award Number:2021A1515010422South China University of Technology。
文摘Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression,but little is known about the mechanism.A key transcription factor in hematopoiesis,MYB,has been reported to increase abnormally in several types of aggressive blood disorders including CML.Methods:This study used a zebrafish model to explore the relationship between BCR/ABL1 and c-myb in CML progression.A CML zebrafish model was crossed with a c-myb hyperactivity transgenic line.Results:It was found that both exogenous BCR/ABL1 and c-myb could up-regulate the expression of neutrophil-related genes.More seriously,neutrophil accumulation was observed when BCR/ABL1 was combined with c-myb overexpression.Further studies showed that c-myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c-myb dependent.Taking advantage of this inheritable in vivo model,it was shown that a combination of imatinib and flavopiridol,a cyclin-dependent kinase inhibitor targeting MYB,could more effectively alleviate the aggressive phenotype of the double transgene line.Conclusion:In summary,this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression.The model used in the study could be helpful in high-throughput drug screening in CML transformation.
基金supported by the National Key Research and Development Program of China(Nos.2022YFC2402900 and 2022YFC2402901)the Fundamental Research Funds for the Central Universities(No.226-2022-00213)the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMD23H300001).
文摘This study aims to gain insight into the DNA-specific recognition mechanism of c-Myb transcription factor during the regulation of cell early differentiation and proliferation.Therefore,we chose the chicken myeloid gene,mitochondrial import protein 1(mim-1),as a target to study the binding specificity between potential dual-Myb-binding sites.The c-Myb-binding site in mim-1 is a pseudo-palindromic sequence AACGGTT,which contains two AACNG consensuses.Simulation studies in different biological scenarios revealed that c-Myb binding with mim-1 in the forward strand(complex F)is more stable than that in the reverse strand(complex R).The principal component analysis(PCA)dynamics trajectory analyses suggested an opening motion of the recognition helices of R2 and R3(R2R3),resulting in the dissociation of DNA from c-Myb in complex R at 330 K,triggered by the reduced electrostatic potential on the surface of R2R3.Furthermore,the DNA confirmation and hydrogen-bond interaction analyses indicated that the major groove width of DNA increased in complex R,which affected on the hydrogenbond formation ability between R2R3 and DNA,and directly resulted in the dissociation of DNA from R2R3.The steered molecular dynamics(SMD)simulation studies also suggested that the electrostatic potential,major groove width,and hydrogen bonds made major contribution to the DNA-specific recognition.In vitro trials confirmed the simulation results that c-Myb specifically bound to mim-1 in the forward strand.This study indicates that the three-dimensional(3D)structure features play an important role in the DNA-specific recognition mechanism by c-Myb besides the AACNG consensuses,which is beneficial to understanding the cell early differentiation and proliferation regulated by c-Myb,as well as the prediction of novel c-Myb-binding motifs in tumorigenesis.
