TITLE:
ATP binding cassette C1 (ABCC1/MRP1)-mediated drug efflux contributes to disease progression in T-lineage acute lymphoblastic leukemia
AUTHORS:
Stuart S. Winter, Jerec Ricci, Li Luo, Debbie M. Lovato, Hadya M. Khawaja, Tasha Serna-Gallegos, Natalie DeBassige, Richard S. Larson
KEYWORDS:
ATP Binding Cassette Proteins C1 and B1; Multi-Drug Resistance; T-Lineage Acute Lymphoblastic Leukemia
JOURNAL NAME:
Health,
Vol.5 No.5A,
May
27,
2013
ABSTRACT: Purpose: In acute
lymphoblastic leukemia (ALL), multidrug resistance is often mediated by AT- Pase
Binding Cassette (ABC) proteins, which principally involve ABCC1 (multidrug
resistance protein 1, MRP1) and ABCB1 (multidrug resistance 1, MDR1). However, direct comparisons between the
differential effects of ABCC1 and ABCB1 have been difficult, since identical
cell lines with differential expression of these transporters have not been
developed. Experimental Design: In this study, we developed and compared the
biological profiles of Jurkat cell lines that
selectively over-expressed ABCC1 and ABCB1. Vincristine (VCR) plays an
important role in the treatment of T-lineage ALL (T-ALL), and is often the
first drug given to newly-diagnosed patients. Because of its importance in
treatment, we provide descalating, sub-lethal doses of VCR to Jurkat cells,
and extended our observations to expression profiling of newly diagnosed patients
with T-ALL. Results: We found that VCR-resistant cells over-expressed ABCC1
nearly 30-fold. The calcein AM assay confirmed that VCR-resistant cells
actively extruded VCR, and that ABCC1-mediated
drug resistance conferred a different spectrum of multidrug resistance
than other T-ALL induction agents. siRNA
experiments that blocked ABCC1 export confirmed that VCR resistance
could be reversed in vitro. Analyses
of T-lymphoblasts obtained from 100 newly diagnosed T-ALL patients treated on
Children’s Oncology Group Phase III studies
9404 and AALL0434 that induction failure could be could be partially explained
by the over-expression of ABCC1 and ABCB1. Conclusions: Taken together, these results suggest that over-expression of ABC
transporters plays a contributing role in mediating treatment failure
in T-ALL, and underscore the need to employ alternate treatment approaches in
patients for whom induction failed or for those with relapsed disease.