ABCA3 as a Possible Cause of Drug Resistance in Childhood Acute Myeloid Leukemia

Abstract

Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters that function as drug efflux pumps. The majority of these proteins have not yet been examined in malignant diseases. Experimental Design: A newly developed microarray for the simultaneous quantification of 38 ABC transporter genes and Taqman real-time PCR was used to analyze the expression of ABC transporters in pediatric AML and healthy bone marrow. Small interfering RNA was used to verify the role of ABCA3 in drug resistance. Results: Using the microarray, we identified four new ABC transporters, which were overexpressed in many AML samples compared with healthy bone marrow: ABCA2, ABCA3, ABCB2, and ABCC10. The overexpression of these four genes was verified by real-time PCR in 42 samples from children with AML and 18 samples of healthy bone marrow. The median expression of ABCA3 was three times higher in 21patients who had failed to achieve remission after the first course of chemotherapy than in a well-matched group of 21 patients who had achieved remission at this stage (P = 0.023). Incubation of cell lines with a number of different cytostatic drugs induced an up-regulation of ABCA3. Down-regulation of ABCA3 by small interfering RNA sensitized cells to doxorubicin. Conclusion: Our results show that ABCA2, ABCA3, ABCB2, and ABCC10 are overexpressed in childhood AML compared with healthy bone marrow. ABCA3 is the most likely transporter to cause drug resistance.

Use of arrays to investigate the contribution of ATP-binding cassette transporters to drug resistance in cancer chemotherapy and prediction of chemosensitivity

“…However, correlation analysis between ABC transporter expression and the clinical outcome did not generate any statistically significant differences in the ALL. Although ABCA3 knock-down in the osteosarcoma cell line 143B by siRNA appeared to generate a significant increase in cellular sensitivity to Adriamycin [33,35], it did not result in any survival effect in response to vinblastine and methotrexate. Knock-down of ABCA2 alone in 143B cells did not appear to have any effect on survival in response to Adriamycin, vinblastine, or methotrexate.…”

“…The same array was also used to profile ABC transporter expression and its correlation to clinical responses of 42 childhood acute myeloid leukemia (AML) patients [33]. It was found that, of all 38 human ABC transporters examined, only ABCA3 had significant correlation of over-expression to poor response ( Table 4), suggesting that ABCA3 may contribute to clinical drug resistance in AML.…”

“…Knocking down ABCA3 expression in the osteosarcoma cell line 143B with siRNA caused a statistically significant increase in sensitivity to Adriamycin. Nevertheless, this increase in sensitivity is very small (<20%) [33]. Because ABCA3 is normally located at intracellular membranes [34], it seems unlikely to mediate drug resistance by directly effluxing drugs as do the traditional ABC drug transporters such as ABCB1 and ABCC1.…”

Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration

“…25 Likewise, drug-resistant variants of human T-lymphoblastic cell lines displayed an increase in ABCA3 expression levels in comparison with the parental lines, in this study due to transcriptional upregulation. 26 Furthermore, utilizing RT/PCR Steinbach et al 27 detected ABCA3 expression in a cohort of 42 pediatric AML samples, and reported significantly higher levels of ABCA3 in 21 patients with poor treatment outcome, compared to 21 patients who benefited from chemotherapy. Finally, in addition to the data of this report, significant ABCA3 expression was identified in cells of epithelial neoplasms such as neuroblastoma and breast cancer.…”

ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia

“…The data suggest that drug-effluxmediated drug resistance of leukemic stem cells may be conferred by many members of the ABC family of membrane transporters with possibly promiscuous action on different chemotherapeutical compounds. The conserved expression of many members of the ABCA family and their emerging role in drug resistance 70 could be of particular importance in this regard and warrants future investigations to further elucidate the role of this class of transporters in drug resistance.…”