OBJECTIVE: Overexpression of members of the adenosine triphosphate binding cassette (ABC) transporter superfamily has been implicated in multidrug resistance in cancer, but results in acute myeloid leukemia (AML) have been inconsistent. We investigated the expression and activity of ABC transporters in patient total blasts and subpopulations along the leukemic stem cell hierarchy. MATERIALS AND METHODS: Using quantitative reverse transcriptase polymerase chain reaction, we measured expression of the ABC transporter superfamily in the blast cells from AML patients prior to chemotherapy. In addition, we measured ex vivo daunorubicin resistance of subpopulations with or without ABC inhibitors. RESULTS: In the total blasts, no consistent difference was observed in 18 patients achieving complete remission (CR) and 13 patients who were refractory to induction chemotherapy (NR). However, among the subpopulation of CD34(+)CD38(-) AML cells (candidate "leukemic stem cells"), elevated expression of MDR1 and/or BCRP1, two ABC transporters associated with drug resistance, was found in 8 of 10 NR patients as compared to 0 of 7 CR patients. No such association was observed in the more differentiated CD34(+)CD38(+) or CD34(-) subpopulations. There was no significant difference in MRP1 expression between CR and NR patient samples in any of the subpopulations examined. The increased expression of MDR1 and BCRP1 in leukemic cells correlated with increased cellular daunorubicin resistance, which could be reversed by the ABC transporter inhibitors verapamil and PSC-833. CONCLUSION: Expression of MDR1 and BCRP1 in leukemic stem cells correlates with chemotherapy response both at the cellular level and in AML patients.
OBJECTIVE: Overexpression of members of the adenosine triphosphate binding cassette (ABC) transporter superfamily has been implicated in multidrug resistance in cancer, but results in acute myeloid leukemia (AML) have been inconsistent. We investigated the expression and activity of ABC transporters in patient total blasts and subpopulations along the leukemic stem cell hierarchy. MATERIALS AND METHODS: Using quantitative reverse transcriptase polymerase chain reaction, we measured expression of the ABC transporter superfamily in the blast cells from AMLpatients prior to chemotherapy. In addition, we measured ex vivo daunorubicin resistance of subpopulations with or without ABC inhibitors. RESULTS: In the total blasts, no consistent difference was observed in 18 patients achieving complete remission (CR) and 13 patients who were refractory to induction chemotherapy (NR). However, among the subpopulation of CD34(+)CD38(-) AML cells (candidate "leukemic stem cells"), elevated expression of MDR1 and/or BCRP1, two ABC transporters associated with drug resistance, was found in 8 of 10 NR patients as compared to 0 of 7 CR patients. No such association was observed in the more differentiated CD34(+)CD38(+) or CD34(-) subpopulations. There was no significant difference in MRP1 expression between CR and NR patient samples in any of the subpopulations examined. The increased expression of MDR1 and BCRP1 in leukemic cells correlated with increased cellular daunorubicin resistance, which could be reversed by the ABC transporter inhibitors verapamil and PSC-833. CONCLUSION: Expression of MDR1 and BCRP1 in leukemic stem cells correlates with chemotherapy response both at the cellular level and in AMLpatients.
Authors: Kambiz Bagheri; Kamran Alimoghadam; Ali Akbar Pourfathollah; Zuhair Muhammad Hassan; Jamshid Hajati; Seyyed Mohammad Moazzeni Journal: Pathol Oncol Res Date: 2008-09-20 Impact factor: 3.201
Authors: Patrick K Campbell; Yang Zong; Shengping Yang; Sheng Zhou; Jeffrey E Rubnitz; Brian P Sorrentino Journal: Leuk Res Date: 2011-10 Impact factor: 3.156
Authors: Jo Ishizawa; Kensuke Kojima; Dhruv Chachad; Peter Ruvolo; Vivian Ruvolo; Rodrigo O Jacamo; Gautam Borthakur; Hong Mu; Zhihong Zeng; Yoko Tabe; Joshua E Allen; Zhiqiang Wang; Wencai Ma; Hans C Lee; Robert Orlowski; Dos D Sarbassov; Philip L Lorenzi; Xuelin Huang; Sattva S Neelapu; Timothy McDonnell; Roberto N Miranda; Michael Wang; Hagop Kantarjian; Marina Konopleva; R Eric Davis; Michael Andreeff Journal: Sci Signal Date: 2016-02-16 Impact factor: 8.192
Authors: Peter Valent; Dominique Bonnet; Ruggero De Maria; Tsvee Lapidot; Mhairi Copland; Junia V Melo; Christine Chomienne; Fumihiko Ishikawa; Jan Jacob Schuringa; Giorgio Stassi; Brian Huntly; Harald Herrmann; Jean Soulier; Alexander Roesch; Gerrit Jan Schuurhuis; Stefan Wöhrer; Michel Arock; Johannes Zuber; Sabine Cerny-Reiterer; Hans E Johnsen; Michael Andreeff; Connie Eaves Journal: Nat Rev Cancer Date: 2012-10-11 Impact factor: 60.716