Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric oncoprotein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly promyelocytic leukemia protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa-associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies.

Figure 1.

Elimination of leukemic blasts and LICs is necessary for definitive cure of APL. LICs posses high self-renewal capability and give rise to leukemic blasts that form the bulk of the disease (middle). Both ATRA and ATO promote remission of disease by targeting leukemic blasts. Pharmacological doses of ATRA predominantly drive differentiation of leukemic blasts, but are unable to efficiently eliminate LICs that can drive disease relapse (right). In contrast, ATO induces both apoptosis and differentiation of leukemic blasts and can also target LICs and is therefore more effective that ATRA as a monotherapy (left). ATRA acts synergistically with ATO and/or CT, and these combination therapies definitively cure APL in the vast majority of cases (dashed arrow).

Figure 2.

Mechanisms of proteolysis of PML-RARa by ATRA and ATO. ATRA induces degradation of RARa and PML-RARa via the RARa moiety. ATO induces degradation of PML and PML-RARa via the PML moiety.

Figure 3.

Rationale for using arsenic trioxide ATO to eliminate LICs in CML. CML is driven by the Bcr-Abl oncoprotein that displays aberrant tyrosine kinase signaling. Tyrosine kinase inhibitors (TKI) such as imatinib can block aberrant signaling and prevent the formation of leukemic cells, but they do not eliminate LICs, thus requiring continuous treatment, inevitably resulting in resistance and relapse. ATO may synergize with TKI to eliminate LICs, thereby curing the disease.