BACKGROUND: A major issue in the treatment of acute myeloid leukemia is resistance to chemotherapeutic drugs. An increasing number of ATP-Binding-Cassette transporters have been demonstrated to cause resistance to cancer drugs. The aim of this study was to highlight the putative role of other ATP-Binding-Cassette transporters in primary chemoresistant acute myeloid leukemia. DESIGN AND METHODS: In the first part of this study, using taqman custom arrays, we analyzed the relative expression levels of 49 ATP-Binding-Cassette genes in 51 patients divided into two extreme cohorts, one very sensitive and one very resistant to chemotherapy. In the second part of this study, we evaluated the prognostic impact, in a cohort of 281 patients, of ATP-Binding-Cassette genes selected in the first part of the study. RESULTS: In the first part of the study, six genes (ATP-Binding-CassetteA2, ATP-Binding-CassetteB1, ATP-Binding-CassetteB6, ATP-Binding-CassettC13, ATP-Binding-CassetteG1, and ATP-Binding-CassetteG2) were significantly over-expressed in the resistant group compared with the sensitive group. In the second cohort, overexpression of 5 of these 6 ATP-Binding-Cassette genes was correlated with outcome in univariate analysis, and only the well-known ATP-Binding-CassetteB1 and G2, and the new ATP-Binding-CassetteG1 in multivariate analysis. Prognosis decreased remarkably with the number of these over-expressed ABC genes. Complete remission was achieved in 71%, 59%, 54%, and 0%, (P=0.0011) and resistance disease in 21%, 37%, 43%, and 100% (P<0.0001) of patients over-expressing 0, 1, 2, or 3, ABC genes, respectively. The number of ATP-Binding-Cassette genes expressed, among ATP-Binding-CassetteB1, G1, and G2, was the strongest prognostic factor correlated, in multivariate analysis, with achievement of complete remission (P=0.01), resistant disease (P=0.01), and overall survival (P=0.02). CONCLUSIONS: Using expression profiling, we have emphasized the diversity of ATP-Binding-Cassette transporters that cooperate to promote chemoresistance rather than overexpression of single transporters and the putative role of new ATP-Binding-Cassette tranporters, such as ATP-Binding-CassetteG1. Modulation of these multiple transporters might be required to eradicate leukemic cells.
BACKGROUND: A major issue in the treatment of acute myeloid leukemia is resistance to chemotherapeutic drugs. An increasing number of ATP-Binding-Cassette transporters have been demonstrated to cause resistance to cancer drugs. The aim of this study was to highlight the putative role of other ATP-Binding-Cassette transporters in primary chemoresistant acute myeloid leukemia. DESIGN AND METHODS: In the first part of this study, using taqman custom arrays, we analyzed the relative expression levels of 49 ATP-Binding-Cassette genes in 51 patients divided into two extreme cohorts, one very sensitive and one very resistant to chemotherapy. In the second part of this study, we evaluated the prognostic impact, in a cohort of 281 patients, of ATP-Binding-Cassette genes selected in the first part of the study. RESULTS: In the first part of the study, six genes (ATP-Binding-CassetteA2, ATP-Binding-CassetteB1, ATP-Binding-CassetteB6, ATP-Binding-CassettC13, ATP-Binding-CassetteG1, and ATP-Binding-CassetteG2) were significantly over-expressed in the resistant group compared with the sensitive group. In the second cohort, overexpression of 5 of these 6 ATP-Binding-Cassette genes was correlated with outcome in univariate analysis, and only the well-known ATP-Binding-CassetteB1 and G2, and the new ATP-Binding-CassetteG1 in multivariate analysis. Prognosis decreased remarkably with the number of these over-expressed ABC genes. Complete remission was achieved in 71%, 59%, 54%, and 0%, (P=0.0011) and resistance disease in 21%, 37%, 43%, and 100% (P<0.0001) of patients over-expressing 0, 1, 2, or 3, ABC genes, respectively. The number of ATP-Binding-Cassette genes expressed, among ATP-Binding-CassetteB1, G1, and G2, was the strongest prognostic factor correlated, in multivariate analysis, with achievement of complete remission (P=0.01), resistant disease (P=0.01), and overall survival (P=0.02). CONCLUSIONS: Using expression profiling, we have emphasized the diversity of ATP-Binding-Cassette transporters that cooperate to promote chemoresistance rather than overexpression of single transporters and the putative role of new ATP-Binding-Cassette tranporters, such as ATP-Binding-CassetteG1. Modulation of these multiple transporters might be required to eradicate leukemic cells.
Authors: E Solary; B Witz; D Caillot; P Moreau; B Desablens; J Y Cahn; A Sadoun; B Pignon; C Berthou; F Maloisel; D Guyotat; P Casassus; N Ifrah; Y Lamy; B Audhuy; P Colombat; J L Harousseau Journal: Blood Date: 1996-08-15 Impact factor: 22.113
Authors: E Wattel; E Solary; B Hecquet; D Caillot; N Ifrah; A Brion; B Mahé; N Milpied; M Janvier; A Guerci; H Rochant; C Cordonnier; F Dreyfus; A Buzyn; L Hoang-Ngoc; A M Stoppa; N Gratecos; A Sadoun; A Stamatoulas; H Tilly; P Brice; F Maloisel; B Lioure; B Desablens; P Fenaux Journal: Br J Haematol Date: 1998-09 Impact factor: 6.998
Authors: C P Leith; K J Kopecky; J Godwin; T McConnell; M L Slovak; I M Chen; D R Head; F R Appelbaum; C L Willman Journal: Blood Date: 1997-05-01 Impact factor: 22.113
Authors: Leilei Tang; Saskia M Bergevoet; Christian Gilissen; Theo de Witte; Joop H Jansen; Bert A van der Reijden; Reinier A P Raymakers Journal: BMC Pharmacol Date: 2010-09-13
Authors: H S Chan; G DeBoer; J J Thiessen; A Budning; J E Kingston; J M O'Brien; G Koren; E Giesbrecht; G Haddad; Z Verjee; J L Hungerford; V Ling; B L Gallie Journal: Clin Cancer Res Date: 1996-09 Impact factor: 12.531
Authors: Brian C Shaffer; Jean-Pierre Gillet; Chirayu Patel; Maria R Baer; Susan E Bates; Michael M Gottesman Journal: Drug Resist Updat Date: 2012-03-11 Impact factor: 18.500
Authors: Katalin Kiss; Anna Brozik; Nora Kucsma; Alexandra Toth; Melinda Gera; Laurence Berry; Alice Vallentin; Henri Vial; Michel Vidal; Gergely Szakacs Journal: PLoS One Date: 2012-05-24 Impact factor: 3.240