ABC transporters in normal and malignant stem cells.

Abstract

Acute myelogenous leukemia is a disease originating from normal hematopoietic CD34+CD38- progenitor cells. Incomplete eradication of these primitive cells may eventually lead to disease relapse. Drug efflux by ABC-transporters is a well-established mechanism by which leukemic cells escape chemotherapeutical eradication. We confirmed that ABCB1 and ABCG2 are involved in transport of chemotherapeutical drugs from normal and leukemic CD34+CD38- primitive cells, but it became clear that additional drug efflux mechanisms must be active in leukemic primitive cells. To identify additional drug efflux mechanisms we studied the expression of all ABC-transporters in CD34+CD38- cells. In normal CD34+CD38- cells 36/45 ABC-transporters were expressed. Among these expressed genes the known multidrug resistance ABC-transporters were found but in addition we found many members not described to be expressed on stem cells. In leukemic CD34+CD38- cells the ABC-transporter profile was largely conserved. Furthermore, we determined the expression pattern of ABC-transporters during exposure to antileukemic drugs. Short-term exposure to anthracyclines rapidly induced a large range of ABC-transporters in leukemic progenitor cells. These induced transporters included both known drug transporters as well as transporters not previously associated with drug-transport or -resistance. These findings challenge the rationale of inhibition of single transporters to circumvent drug resistance of leukemic progenitors. Next to anthracyclines, Ara-C is one of the most important antileukemic drugs currently available for the treatment of AML. Many mechanisms for resistance to Ara-C have been identified, but an effect on ABC-transporters has never been described. A number of ABC-transporters were induced after exposure to Ara-C, ABCC6 showed the strongest induction. Further studies are warranted to unravel the mechanism behind the Ara-C resistance in ABCC6 expressing cells. The identification of previously unrecognized ABC-transporters in leukemic primitive cells offers the basis for future studies investigating the functional role of these ABC-transporters in resistance and their usefulness as therapeutically targets.