Haematologica, Vol 94, Issue 11, 1528-1536 doi:10.3324/haematol.2009.008631
Copyright © 2009 by Ferrata Storti Foundation
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Chronic Myeloid Leukemia

ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug

Bjoern Chapuy1,2, Melanie Panse1, Ulf Radunski1, Raphael Koch1, Dirk Wenzel3, Nobuya Inagaki4, Detlef Haase1, Lorenz Truemper1, Gerald G. Wulf1

1 Dept. of Hematology and Oncology, Georg-August-University Goettingen, Germany
3 Dept. of Neurobiology, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany
4 Department of Diabetes and Clinical Nutrition, Kyoto University, Kyoto, Japan

Correspondence: Gerald G. Wulf, Department Hematology and Oncology, Georg-August-University, Goettingen Robert-Koch-Str.40, 37075 Goettingen, Germany. E-mail:gwulf{at}med.uni-goettin-gen.de

Background: Inhibition of BCR-ABL tyrosine kinase activity has evolved as a mainstay of therapy for patients with chronic myeloid leukemia. However, a fraction of leukemic cells persists under targeted therapy and can lead to disease progression on cessation of treatment.

Design and Methods: We analyzed bone marrow progenitor cells with the side population phenotype, and characterized the role of the intracellular ABC transporter A3 in imatinib detoxification.

Results: BCR-ABL-positive leukemic cells contribute to the side population cell compartment in untreated patients. Such leukemic side population cells, as well as CD34-positive progenitors from chronic myeloid leukemia samples, strongly express the intracellular ABCA3. Functionally, ABCA3 levels are critical for the susceptibility of chronic myeloid leukemia blast cell lines to specific BCR-ABL inhibition by imatinib. The transporter is localized in the limiting membrane of lysosomes and multivesicular bodies, and intracellular [14C]-labeled imatinib accumulates in such organelles. The lysosomal storage capacity increases with ABCA3 expression, thus regulating imatinib sequestration.

Conclusions: The intracellular ABC transporter A3 is expressed in chronic myeloid leukemia progenitor cells and may contribute to intrinsic imatinib resistance by facilitating lysosomal sequestration in chronic myeloid leukemia cells.

Key words: imatinib resistance, ABC transporter, lysosome, chronic myeloid leukemia, side population.