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


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.
Chapuy
Bjoern
B
Department Hematology and Oncology, Georg-August-University, Goettingen Robert-Koch-Str.40, 37075 Goettingen, Germany.
Panse
Melanie
M
Radunski
Ulf
U
Koch
Raphael
R
Wenzel
Dirk
D
Inagaki
Nobuya
N
Haase
Detlef
D
Truemper
Lorenz
L
Wulf
Gerald G
GG
D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000502:physiology*; D001549:Benzamides; D045744:Cell Line, Tumor; D004351:Drug Resistance; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate