title: High functional P-glycoprotein activity is more often present in T-cell acute lymphoblastic leukaemic cells in adults than in children.
abstract: There is a distinct difference in prognosis between childhood versus adult acute lymphoblastic leukaemia (ALL). To define whether multidrug resistance (MDR) genes might contribute to this distinction, the expression and functional activity of P-glycoprotein (P-gp) and MDR associated proteins (MRP) were determined with RT-PCR (MDR-1, MRP1, MRP2, MRP3) and flow cytometry (P-gp and MRP). Patient samples were obtained from 36 children and 35 adults with de novo ALL. Of these patients, 38 showed a T-lineage and 33 showed a B-lineage immunophenotype. In the samples, large variability in P-gp activity (0.8-4.9) and MRP activity (1.1-13.9) was observed. Most T-ALL patients with high P-gp activity were adults (89%). The mRNA expression of MDR-1 correlated weakly with P-gp activity. In contrast, MRP activity did not correlate with the mRNA expression of MRP1, MRP2 and MRP3. In T-ALL, a worse overall survival and event-free survival was observed with increasing P-gp activity. P-gp activity had no prognostic impact in B-lineage ALL. In addition, high MRP activity did not influence treatment outcome in either T- or B-lineage ALL. Multivariate Cox regression analysis, showed P-gp activity to be the only unfavourable prognostic factor for overall survival in T-ALL. In conclusion, this study demonstrates the prognostic relevance of P-gp activity in T-ALL. Since the majority of the patients with high P-gp activity were adults, P-gp might contribute to the poor prognosis of adult T-ALL.
authors.affiliation: Department of Paediatric Haematology and Oncology, University Hospital Groningen, Groningen, The Netherlands.
authors.forename: Sabine L A
authors.initials: SL
authors.lastname: Plasschaert
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
authors.forename: Dorina M
authors.initials: DM
authors.lastname: van der Kolk
authors.forename: Anjo J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Sluiter
authors.forename: Simon M G
authors.initials: SM
authors.lastname: Daenen
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Willem A
authors.initials: WA
authors.lastname: Kamps
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015448:Leukemia, B-Cell / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D015458:Leukemia, T-Cell / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3; C421109:multidrug resistance-associated protein 1