title: Genetic alterations determine chemotherapy resistance in childhood T-ALL: modelling in stage-specific cell lines and correlation with diagnostic patient samples.
abstract: Acquired drug resistance eventually leads to treatment failure in T-cell acute lymphoblastic leukaemia (T-ALL). Immunophenotypic and cytogenetic heterogeneities within T-ALL influence susceptibility to cytotoxic therapy, and little is known about the mechanisms of drug resistance at specific stages of T-cell ontogeny. We developed tolerance to therapeutic concentrations of daunorubicin (DNR) and L-asparaginase (L-asp) in Jurkat (CD1a(-), sCD3(+)) and Sup T1 (CD1a(+), sCD3(-)) cell lines, having respective 'mature' and 'cortical' stages of developmental arrest. DNR resistant cells acquired multidrug resistance: 310-fold increased resistance to vincristine (VCR) and a 120-fold increased resistance to prednisolone (PRED). Microarray analysis identified upregulation of asparagine synthetase (ASNS) and argininosuccinate synthase 1 (ASS1) to cell lines with acquired resistance to L-asp, and in the case of DNR, upregulation of ATP-binding cassette B1 (ABCB1). Suppression of ABCB1, ASNS and ASS1 by RNA interference revealed their functional relevance to acquired drug resistance. Expression profiling of these genes in 80 T-ALL patients showed correlation with treatment response. This study expands the pool of available drug resistant cell lines having cortical and mature stages of developmental arrest, introduces three new drug resistant T-ALL cell lines, and identifies gene interactions leading to L-asp and DNR resistance.
authors.affiliation: Department of Pathology, University of New Mexico Cancer Research and Treatment Center, Albuquerque, NM 87112, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Estes
authors.forename: Debbie M
authors.initials: DM
authors.lastname: Lovato
authors.forename: Hadya M
authors.initials: HM
authors.lastname: Khawaja
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Winter
authors.forename: Richard S
authors.initials: RS
authors.lastname: Larson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D001124:Argininosuccinate Synthase / Q000235:genetics; D001215:Asparaginase / Q000627:therapeutic use; D001217:Aspartate-Ammonia Ligase / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D003630:Daunorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D019450:Genes, MDR; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011239:Prednisolone / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D034741:RNA, Small Interfering; D014750:Vincristine; D011239:Prednisolone; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase; D001124:Argininosuccinate Synthase; D003630:Daunorubicin