UBC Theses and Dissertations
ABC transporters as predictive factors for chemotherapeutic response in acute myeloid leukemia Ho, Maria Ming Chee
Multidrug Resistance (MDR), resistance to multiple chemotherapeutic drugs, is a major problem in the treatment of acute myeloid leukemia (AML) . Overexpression of members of the ATPBinding- Cassette (ABC) transporter superfamily has been associated with clinical MDR and failure of conventional chemotherapy. The work in this thesis was the first in investigating expression of ABC transporters and functional effects of their modulation in AML subpopulations along the leukemic stem cell hierarchy: CD34+CD38- (primitive and disease maintaining), CD34+CD38+ (differentiating progenitors), and CD34- (depleted of progenitors). An initial profiling of mRNA expression of the 47 human ABC transporters in total de novo blasts by RT Real-Time PCR showed no consistent differences between patients who subsequently achieved complete remission following conventional remission induction chemotherapy (responders) and patients who remained refractory (non-responders). Subsequent profiling of isolated subpopulations, however, revealed elevated expression of MDR1 and/or BCRP1, two main drug-resistance ABC transporters, in the primitive CD34+CD38- fraction of 7/10 non-responders compared to 0/7 responders. To test their functional activity ex vivo, daunorubicin sensitivity with or without ABC modulators was determined in AML subpopulations by the apoptotic assay. I found high ABC-dependent drug resistance, correlated to high MDR1IBCRP1 expression level and reversible by ABC inhibition, in the CD34+CD38- fraction of non-responders compared to responders. This suggests an active functional role of ABC transporters in the primitive, disease-maintaining fraction. Taken as a whole, my studies suggest a prognostic significance of ABC transporters in the primitive CD34+CD38- leukemic subpopulation, and support a modified approach in investigating the value of ABC modulating agents in AML. It may be possible to pre-screen and identify patients for whom ABC transporters is a major factor for MDR before initial treatment, who are most likely to benefit from the combination of conventional chemotherapy and ABC inhibitors. This will be invaluable especially to patients with a normal karyotype (50% of patients), since cytogenetic aberrations currently remain the most useful prognostic marker for AML.
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