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

Abstract

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 [(14)C]-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.

• Authors: Bjoern Chapuy, Melanie Panse, Ulf Radunski, Raphael Koch, Dirk Wenzel, Nobuya Inagaki, Detlef Haase, Lorenz Truemper, Gerald G Wulf
• Journal: Haematologica (Haematologica) Vol. 94 Issue 11 Pg. 1528-36 (Nov 2009) ISSN: 1592-8721 [Electronic] Italy
• PMID: 19880777 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCA3 protein, human
• ATP-Binding Cassette Transporters
• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate

Topics

• ATP-Binding Cassette Transporters (analysis, physiology)
• Benzamides
• Cell Line, Tumor
• Drug Resistance
• Humans
• Imatinib Mesylate
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism, pathology)
• Lysosomes (metabolism)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)