title: Multidrug resistance in relapsed acute myeloid leukemia: evidence of biological heterogeneity.
abstract: BACKGROUND
  Studies of mechanisms mediating resistance to chemotherapy led to the discovery of the multidrug transporter ABCB1 (ATP-binding cassette, subfamily B, member 1), often expressed in leukemic cells of patients with acute myeloid leukemia (AML). Most clinical trials evaluating the strategy of inhibiting efflux-mediated chemotherapeutic resistance have been unsuccessful, clearly indicating the need for a better approach.
  
  
  METHODS
  This study investigated the clinical relevance of 380 genes whose expression has been shown to affect the response to chemotherapy, mostly through in vitro studies, in 11 paired samples obtained at AML diagnosis and at relapse. The expression profiling of these 380 genes was performed using TaqMan-based quantitative reverse-transcription polymerase chain reaction. Patients had a median age of 58 years at diagnosis, a median duration of complete remission of 284.5 days, and a median overall survival of 563 days. Cytogenetic abnormalities were detected at diagnosis in 4 patients, whereas 5 displayed a normal karyotype and 2 were not investigated.
  
  
  RESULTS
  Hierarchical clustering shows that samples taken at diagnosis and relapse clustered in pairs for 6 patients of the 11 studied, suggesting recurrence of the same leukemic blast, whereas for the other 5 patients, the data indicate their relapse blasts arose from different origins. A patient-by-patient analysis of the paired samples led to the striking observation that each had a unique gene signature representing different mechanisms of resistance.
  
  
  CONCLUSIONS
  The data underline the need for personalized molecular analysis to tailor treatment for patients with AML.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chirayu
authors.initials: C
authors.lastname: Patel
authors.forename: Leif
authors.initials: L
authors.lastname: Stenke
authors.forename: Sudhir
authors.initials: S
authors.lastname: Varma
authors.forename: Marita Lagergren
authors.initials: ML
authors.lastname: Lindberg
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.forename: Jan
authors.initials: J
authors.lastname: Sjöberg
authors.forename: Kristina
authors.initials: K
authors.lastname: Viktorsson
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.forename: Ola
authors.initials: O
authors.lastname: Landgren
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gillet
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012008:Recurrence; D055815:Young Adult
chemical_list: C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D005980:Glutathione Reductase
keywords: acquired drug resistance; acute myeloid leukemia; leukemia cell lines; multidrug resistance; therapy-related drug resistance