title: ABCA3 as a possible cause of drug resistance in childhood acute myeloid leukemia.
abstract: BACKGROUND
  A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters that function as drug efflux pumps. The majority of these proteins have not yet been examined in malignant diseases.
  
  
  METHODS
  A newly developed microarray for the simultaneous quantification of 38 ABC transporter genes and Taqman real-time PCR was used to analyze the expression of ABC transporters in pediatric AML and healthy bone marrow. Small interfering RNA was used to verify the role of ABCA3 in drug resistance.
  
  
  RESULTS
  Using the microarray, we identified four new ABC transporters, which were overexpressed in many AML samples compared with healthy bone marrow: ABCA2, ABCA3, ABCB2, and ABCC10. The overexpression of these four genes was verified by real-time PCR in 42 samples from children with AML and 18 samples of healthy bone marrow. The median expression of ABCA3 was three times higher in 21 patients who had failed to achieve remission after the first course of chemotherapy than in a well-matched group of 21 patients who had achieved remission at this stage (P = 0.023). Incubation of cell lines with a number of different cytostatic drugs induced an up-regulation of ABCA3. Down-regulation of ABCA3 by small interfering RNA sensitized cells to doxorubicin.
  
  
  CONCLUSIONS
  Our results show that ABCA2, ABCA3, ABCB2, and ABCC10 are overexpressed in childhood AML compared with healthy bone marrow. ABCA3 is the most likely transporter to cause drug resistance.
authors.affiliation: Children's Hospital, University of Jena, Jena, Germany. Daniel@Steinba.ch
authors.forename: Daniel
authors.initials: D
authors.lastname: Steinbach
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gillet
authors.forename: Axel
authors.initials: A
authors.lastname: Sauerbrey
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.forename: Kristin
authors.initials: K
authors.lastname: Dawczynski
authors.forename: Vincent
authors.initials: V
authors.lastname: Bertholet
authors.forename: Françoise
authors.initials: F
authors.lastname: de Longueville
authors.forename: Felix
authors.initials: F
authors.lastname: Zintl
authors.forename: Jose
authors.initials: J
authors.lastname: Remacle
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D034741:RNA, Small Interfering