Targeting of leukemia-initiating cells in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with peculiar molecular, phenotypic and clinical features and unique therapeutic response to specific treatments. The disease is characterized by a single, pathognomonic molecular event, consisting of the translocation t(15;17) which gives rise to the PML/retinoic acid receptor α (RARα) hybrid protein. The development of this leukemia is mainly related to the fusion oncoprotein PML/RARα, acting as an altered RAR mediating abnormal signalling and repression of myeloid differentiation, with consequent accumulation of undifferentiated promyelocytes. The prognosis of APL has dramatically been improved with the introduction in therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The main effect of these two drugs is linked to the targeting of either RAR moiety of the PML/RARα molecule and induction of cell differentiation (ATRA) or of the PML moiety of the fusion protein and induction of leukemic cell apoptosis, including leukemic progenitors (mostly induced by ATO). These two drugs exhibited excellent synergism and determine a very high rate of durable remissions in low/intermediate-risk APLs, when administered in the absence of any chemotherapeutic drug. The strong synergism and the marked clinical efficacy of these two agents when administered together seem to be related to their capacity to induce PML/RARα degradation and complete eradication of leukemia stem cells.