ABCA3 Expression in AML Blast Cells: Association with Poor Disease Outcome and Intracellular Drug Sequestration.

Analysing the intrinsic drug efflux capacity of leukemic stem cell with the side population (SP) phenotype, we recently found the intracellular ABC transporter ABCA3 expressed in blast cells from patients with acute myeloid leukaemia (AML). Here we extend our observations to a larger cohort of AML samples and addressed the role of ABCA3 for cytostatic drug resistance. Applying quantitative RT/PCR (Taqman), we detected significant levels of ABCA3 in 59 of 92 blast cell samples from 58 pediatric and 34 adult patients with AML. The expression of ABCA3 correlated positively (coefficient 0.83) with the expression of CD34, while there was no association with the acquisition of markers for myeloid and monocytic maturation. As for disease outcome analysed by univariate analysis, we found a significantly worse outcome in both event free survival (p=0.048) and overall survival (p=0.034) for the patients with high-level ABCA3 expression. Functionally, the expression of ABCA3 was restricted to the cytoplasm in the AML blast cells, and co-localisation studies revealed an association with endosomal markers. Ectopic expression of ABCA3 augmented the lysosomal compartment in HEK 293 cells, and enhanced intracellular anthracyclin sequestration into vesicles of the endosomal system. Correspondingly, we observed a significant reduction of cytostatic efficacy from anthracyclins in stably ABCA3 expressing HEK293 cells compared to the parental cell line. In conclusion, we found the intracellular transporter ABCA3 expressed in the blast cells of most patients with AML, and elevated ABCA3 levels associated with poor disease outcome. Functional data revealed intracellular anthracyclin sequestration by ABCA3, suggesting a role of ABCA3 for drug resistance in patients with AML.