Background:Thanks to an improved therapeutic regimen in childhood B-cell precursor acute lymphoblastic leukemia(BCP-ALL),5 year-overall survival now exceeds 90%.Unfortunately,the 25%of children who relapse have an ini...Background:Thanks to an improved therapeutic regimen in childhood B-cell precursor acute lymphoblastic leukemia(BCP-ALL),5 year-overall survival now exceeds 90%.Unfortunately,the 25%of children who relapse have an initial poor prognosis,potentially driven by pre-existing or emerging molecular anomalies.The latter are initially and essentially identified by cytogenetics.However,some subtle alterations are not visible through karyotyping.Methods:Single nucleotide polymorphisms(SNP)array is an alternative way of chromosomal analysis allowing for a more in-depth evaluation of chromosomal modifications such as the assessment of copy number alterations(CNA)and loss of heterozygosity(LOH).This method was applied here in retrospective diagnosis/relapse paired samples from seven children with BCP-ALL and in a prospective cohort of 38 newly diagnosed childhood cases.Results:In the matched study,compared to the initial karyotype,SNP array analysis reclassified two patients as poor prognosis cases.Modulation during relapse was seen for 4 CNA and 0.9 LOH.In the prospective study,SNP reclassified the 10 patients with intermediate karyotype as 7 good prognosis and 3 poor prognosis.Ultimately,in all the children tested,SNP array allowed to identify additional anomalies compared to conventional karyotype,refine its prognostic value and identify some druggable anomalies that could be used for precision medicine.Overall,the anomalies detected could be segregated in four groups respectively involved in B-cell development,cell proliferation,transcription and molecular pathways.Conclusion:SNP therefore appears to be a method of choice in the integrated diagnosis of BCP ALL,especially for patients initially classified as intermediate prognosis.This complementary method of both cytogenetics and high throughput sequencing allows to obtain further classified information and can be useful in case of failure of these techniques.展开更多
B-cell precursor acute lymphoblastic leukemia(BCP-ALL)is characterized by genetic alterations with high heterogeneity.Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed ...B-cell precursor acute lymphoblastic leukemia(BCP-ALL)is characterized by genetic alterations with high heterogeneity.Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology.Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes,such as DUX4 rearrangements,MEF2D rearrangements,ZNF384/ZNF362 rearrangements,NUTM1 rearrangements,BCL2/MYC and/or BCL6 rearrangements,ETV6-RUNX1-like gene expression,PAX5alt(diverse PAX5 alterations,including rearrangements,intragenic amplifications,or mutations),and hotspot mutations PAX5(p.Pro80Arg)with biallelic PAX5 alterations,IKZF1(p.Asn159Tyr),and ZEB2(p.His1038Arg).These molecular subtypes could be classified by gene expression patterns with RNA-seq technology.Refined molecular classification greatly improved the treatment strategy.Multiagent therapy regimens,including target inhibitors(e.g.,imatinib),immunomodulators,monoclonal antibodies,and chimeric antigen receptor T-cell(CAR-T)therapy,are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management.We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.展开更多
基金Nantes University Hospital MEFRALL project,Grant/Award Number:RC_0144。
文摘Background:Thanks to an improved therapeutic regimen in childhood B-cell precursor acute lymphoblastic leukemia(BCP-ALL),5 year-overall survival now exceeds 90%.Unfortunately,the 25%of children who relapse have an initial poor prognosis,potentially driven by pre-existing or emerging molecular anomalies.The latter are initially and essentially identified by cytogenetics.However,some subtle alterations are not visible through karyotyping.Methods:Single nucleotide polymorphisms(SNP)array is an alternative way of chromosomal analysis allowing for a more in-depth evaluation of chromosomal modifications such as the assessment of copy number alterations(CNA)and loss of heterozygosity(LOH).This method was applied here in retrospective diagnosis/relapse paired samples from seven children with BCP-ALL and in a prospective cohort of 38 newly diagnosed childhood cases.Results:In the matched study,compared to the initial karyotype,SNP array analysis reclassified two patients as poor prognosis cases.Modulation during relapse was seen for 4 CNA and 0.9 LOH.In the prospective study,SNP reclassified the 10 patients with intermediate karyotype as 7 good prognosis and 3 poor prognosis.Ultimately,in all the children tested,SNP array allowed to identify additional anomalies compared to conventional karyotype,refine its prognostic value and identify some druggable anomalies that could be used for precision medicine.Overall,the anomalies detected could be segregated in four groups respectively involved in B-cell development,cell proliferation,transcription and molecular pathways.Conclusion:SNP therefore appears to be a method of choice in the integrated diagnosis of BCP ALL,especially for patients initially classified as intermediate prognosis.This complementary method of both cytogenetics and high throughput sequencing allows to obtain further classified information and can be useful in case of failure of these techniques.
基金This work was supported by the National Natural Science Foundation of China(Nos.82070147,81570122,and 81770205)the National Key Research and Development Program(No.2016YFC0902800)+2 种基金the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(No.20161303)the Innovation Foundation for Doctoral Students of Shanghai Jiao Tong University School of Medicine(Research Grant BXJ201815)the Center for HPC at Shanghai Jiao Tong University.The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘B-cell precursor acute lymphoblastic leukemia(BCP-ALL)is characterized by genetic alterations with high heterogeneity.Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology.Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes,such as DUX4 rearrangements,MEF2D rearrangements,ZNF384/ZNF362 rearrangements,NUTM1 rearrangements,BCL2/MYC and/or BCL6 rearrangements,ETV6-RUNX1-like gene expression,PAX5alt(diverse PAX5 alterations,including rearrangements,intragenic amplifications,or mutations),and hotspot mutations PAX5(p.Pro80Arg)with biallelic PAX5 alterations,IKZF1(p.Asn159Tyr),and ZEB2(p.His1038Arg).These molecular subtypes could be classified by gene expression patterns with RNA-seq technology.Refined molecular classification greatly improved the treatment strategy.Multiagent therapy regimens,including target inhibitors(e.g.,imatinib),immunomodulators,monoclonal antibodies,and chimeric antigen receptor T-cell(CAR-T)therapy,are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management.We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.