Resistance to differentiation therapy

Incorporation of all-trans-retinoic acid (ATRA) into the treatment of acute promyelocytic leukemia (APL), a type of acute myeloid leukemia (AML), revolutionized the therapy of cancer and introduced the concept of differentiation therapy in the last decade. ATRA, a physiological metabolite of vitamin A (retinol), induces complete clinical remissions (CR) initially in about 90% of patients with APL. In contrast to the cytotoxic chemotherapeutics, ATRA can selectively induce terminal differentiation of promyelocytic leukemia cells into normal granulocytes without causing bone marrow hypoplasia or exacerbation of the frequently occurring fatal hemorrhagic syndromes in patients with APL. Unfortunately, ATRA-induced remissions are transient and most APL patients become quickly resistant to the therapy and relapse, thus limiting the use of ATRA as a single agent. Based on in vitro, in vivo, and clinical observations, several mechanisms including induction of accelerated metabolism of ATRA, decreased bioavailability and plasma drug levels, point mutations in the ligand-binding domain of PML-RARα fusion protein and other molecular events have been proposed to explain resistance to differentiation therapy by ATRA. Although different compounds, such as phorbol ester (TPA), vitamin D ₃, interferons, and dimethyl sulfoxide can induce differentiation in vitro, ATRA represents the first successful use of differentiation therapy in the clinic; therefore, here we will focus on mechanisms that regulate ATRA-induced myeloid cell differentiation and the molecular mechanisms causing resistance to ATRA and possible clinical approaches to overcome resistance to differentiation.