Acute lymphoblastic leukemia(ALL)is the most common malignancy of childhood.The genomic landscape of pediatric ALL has been extensively characterized,allowing for the identification of distinct molecular subtypes of t...Acute lymphoblastic leukemia(ALL)is the most common malignancy of childhood.The genomic landscape of pediatric ALL has been extensively characterized,allowing for the identification of distinct molecular subtypes of this disease.This in turn has facilitated improvements in risk stratification and tailoring of therapy,resulting in dramatic improvements in survival rates over the past several decades.However,despite these improvements,outcomes remain dismal for the ten percent of patients who continue to fail therapy and relapse.Although the genetic landscape of pediatric ALL is well-understood,increasing evidence suggests that genetic alterations alone are insufficient to promote leukemogenesis and the acquisition of chemoresistance that leads to disease relapse.Instead,cooperating epigenetic alterations are now recognized as important contributors to the aberrant gene expression profiles that are characteristic of the molecular subtypes of ALL,and changes in the epigenetic landscape are now thought to underlie the development of chemoresistance and ultimately disease relapse.This review article focuses on the expanding knowledge of the role of the epigenome in ALL pathogenesis,progression,and response to therapy,and highlights preclinical and clinical efforts to target the epigenome as a means of overcoming chemoresistance and improving outcomes for children with ALL.展开更多
Acute lymphoblastic leukemia(ALL)is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations.With the introduction ...Acute lymphoblastic leukemia(ALL)is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations.With the introduction of intensive multi-agent chemotherapeutic regimens,survival rates for ALL have improved dramatically over the past several decades,though survival rates for adult ALL continue to lag behind those of pediatric ALL.Resistance to chemotherapy remains a significant obstacle in the treatment of ALL,and chemoresistance due to molecular alterations within ALL cells have been described.In addition to these cell-intrinsic factors,the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance,and it is now known that stromal cells within the bone marrow microenvironment,through direct cell-cell interactions and through the release of lymphoid-acting soluble factors,contribute to ALL pathogenesis and chemoresistance.This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context.展开更多
基金This work is supported by a Genentech Foundation Fellowship Award to Meyer LKthe National Cancer Institute(R01 CA193776)to Hermiston ML+2 种基金the Buster Posey Family Foundationthe Campini Foundationthe Pepp Family Foundation.
文摘Acute lymphoblastic leukemia(ALL)is the most common malignancy of childhood.The genomic landscape of pediatric ALL has been extensively characterized,allowing for the identification of distinct molecular subtypes of this disease.This in turn has facilitated improvements in risk stratification and tailoring of therapy,resulting in dramatic improvements in survival rates over the past several decades.However,despite these improvements,outcomes remain dismal for the ten percent of patients who continue to fail therapy and relapse.Although the genetic landscape of pediatric ALL is well-understood,increasing evidence suggests that genetic alterations alone are insufficient to promote leukemogenesis and the acquisition of chemoresistance that leads to disease relapse.Instead,cooperating epigenetic alterations are now recognized as important contributors to the aberrant gene expression profiles that are characteristic of the molecular subtypes of ALL,and changes in the epigenetic landscape are now thought to underlie the development of chemoresistance and ultimately disease relapse.This review article focuses on the expanding knowledge of the role of the epigenome in ALL pathogenesis,progression,and response to therapy,and highlights preclinical and clinical efforts to target the epigenome as a means of overcoming chemoresistance and improving outcomes for children with ALL.
基金Meyer LK is supported by a Genentech Foundation Fellowship Award.Hermiston ML is supported by the National Cancer Institute Grant R01 CA193776the Buster Posey Family Foundation,the Campini Foundation,and the Pepp Family Foundation.
文摘Acute lymphoblastic leukemia(ALL)is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations.With the introduction of intensive multi-agent chemotherapeutic regimens,survival rates for ALL have improved dramatically over the past several decades,though survival rates for adult ALL continue to lag behind those of pediatric ALL.Resistance to chemotherapy remains a significant obstacle in the treatment of ALL,and chemoresistance due to molecular alterations within ALL cells have been described.In addition to these cell-intrinsic factors,the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance,and it is now known that stromal cells within the bone marrow microenvironment,through direct cell-cell interactions and through the release of lymphoid-acting soluble factors,contribute to ALL pathogenesis and chemoresistance.This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context.
