title: Multidrug resistant cells with high proliferative capacity determine response to therapy in acute myeloid leukemia.
abstract: High spontaneous proliferation of acute myeloid leukemia (AML) in vitro is an unfavorable, tumor-specific prognostic factor. We investigated the frequency of drug-resistant tumor cells with high proliferating capacity in de novo AML and analyzed the expression of multiple resistance parameters in relation to the response to chemotherapy and overall survival. Thirty-eight patients were included in this study. P-glycoprotein (P-gp) expression was found in 28/38 patients and was associated with lower intracellular accumulation of DNR (P = 0.0001). Thirty-five out of 38 patients were treated with 1-2 regimens of daunorubicin (DNR)/cytarabine (Ara-C), and 57% attained a complete remission (CR). Failure to achieve a CR correlated with autonomous growth (P = 0.0064), CD34 and P-gp expression alone (P = 0.0005 and P = 0.048 respectively), and with simultaneous expression of P-gp and CD34 (P = 0.0001), but not with expression of the non-P-gp drug resistance associated-protein (p110), the multidrug resistance-associated protein (MRP), Ara-CTP formation or Ara-C incorporation, respectively. AML cells with CD34/P-gp double expression were more frequently observed in samples with high autonomous growth (P = 0.003). The median survival was 6 months in CD34+/P-gp+ patients as compared with 15 months in other AML patients (P = 0.003). In patients with de novo AML who fail on chemotherapy, a population of autonomously proliferating, immature AML cells with a multidrug resistant phenotype can be recognized. These cells thus show primary resistance to chemotherapy and have the potential for rapid regrowth, leading to resistant disease.
authors.affiliation: Department of Hematology, Erasmus University, Rotterdam, The Netherlands.
authors.forename: P A
authors.initials: PA
authors.lastname: te Boekhorst
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
authors.forename: J
authors.initials: J
authors.lastname: van Kapel
authors.forename: K
authors.initials: K
authors.lastname: Nooter
authors.forename: P
authors.initials: P
authors.lastname: Sonneveld
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000208:Acute Disease; D000367:Age Factors; D000704:Analysis of Variance; D015703:Antigens, CD / Q000096:biosynthesis; D018952:Antigens, CD34; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001853:Bone Marrow / Q000473:pathology*; D002455:Cell Division; D002478:Cells, Cultured; D003561:Cytarabine / Q000008:administration & dosage / Q000378:metabolism; D003630:Daunorubicin / Q000008:administration & dosage / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000473:pathology*; D011237:Predictive Value of Tests; D012074:Remission Induction; D015996:Survival Rate
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D003561:Cytarabine; D003630:Daunorubicin