ABC Expression As Additionally Marker To Monitoring Response In CML - A Preliminary Study

Chronic myeloid leukemia (CML) is a mieloproliferative disorder characterized by the presence of the BCR-ABL gene fusion, which encodes an oncoprotein with a deregulated tyrosine kinase activity. This oncoprotein became the main therapeutic target of the disease with the introduction of specific tyrosine kinase inhibitors (TKIs). Additionally, the fusion gene expression level is used as a monitoring tool to determine the molecular response of each patient. However, several patients show incomplete or loss of response and even in some cases resistance to the TKI therapy. Leukemia stems cells, as normal stem cells, could present ABC transporters to protect them-self against therapeutic agents which could contribute to therapeutic failure. One of the most described ABC transporters is PgP and Imatinib and other TKIs are substrates for these efflux transporters. The precise link between ABC transports and response to therapy in CML is not fully understood.

The aims of this work were to evaluate the expression levels of ABC transporters, namely PgP and BCRP, in CML patients and to correlate them with the BCR-ABL levels.

We examined in CD34+ cells obtained from peripheral blood of 46 patients with CML, the expression levels of PgP and BCRP by flow cytometry using monoclonal antibodies. The BCR-ABL quantification was determined according to the international guidelines for CML management and at the time point of the study 26 patients (56,5%) present a positive quantification of BCR-ABL while the remain 20 patients (43,5%) were BCR-ABL negative. The median patient age at diagnosis was approximately 48 years (24–88), gender M/F=24/22, and 95% of the patients are under treatment with TKIs.

Our preliminary results show that patients with no detectable BCR-ABL mRNA (negative) present a higher percentage of CD34+ cells than patients positive for this fusion gene. Furthermore, 80% of these negative patients (n=16) expressed PgP and/or BCRP in cell membrane and 56,2% of these patients would present a positive quantification of BCR-ABL levels in the first 6 months and 75% at the end of one year.

These results suggest that the presence of ABC transporters in CD34+ cells of patients without detectable levels of BCR-ABL could constitute an earlier marker of loss of response and may be an additional tool for monitoring response in CML patients. However, further analysis should be performed, namely an increased number of patients, to confirm our results and the clinical relevance.