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Eradication of acute promyelocytic leukemia-initiating cells by PML/RARA-targeting
1Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.
Abstract:
Acute promyelocytic leukemia (APL) is characterized by a t(15;17) translocation that yields a PML/RARA fusion protein. Expression of PML/RARA, a potent transcriptional repressor, induces APL in mice. Both retinoic acid (RA) and arsenic trioxide directly target PML/RARA-mediated transcriptional repression and protein stability, inducing rapid differentiation of the promyelocytes and clinical remission in most APL patients. RA also triggers growth arrest and progressive clearance of leukemia initiating cells (LIC), both ex vivo and in vivo. Suboptimal RA concentrations or expression of the PLZF/RARA variant allows complete RA-induced differentiation, but neither LIC clearance nor disease remission. Thus, RA-induced differentiation and LIC clearance may be uncoupled. The RA/arsenic trioxide association, which dramatically synergizes for PML/RARA degradation but not for differentiation, rapidly clears LIC in a proteasome-dependent manner, resulting in APL eradication in murine models and patients. Collectively, these results demonstrate that LIC clearance, which mirrors PML/RARA degradation, is the primary basis for APL cure by the RA/arsenic trioxide association, rather than differentiation. Oncogene degradation could be a generally applicable therapeutic strategy to clear LICs in several types of tumors.
Insights
Retinoic acid and arsenic trioxide treat acute promyelocytic leukemia (APL) by clearing leukemia initiating cells (LICs), not just by promoting differentiation. This targeted oncogene degradation offers a promising strategy for APL eradication.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Therapeutics
Background:
- Acute promyelocytic leukemia (APL) is driven by the PML/RARA fusion protein, a transcriptional repressor.
- Retinoic acid (RA) and arsenic trioxide are established APL treatments targeting PML/RARA.
- The roles of differentiation versus leukemia-initiating cell (LIC) clearance in APL treatment remain debated.
Purpose of the Study:
- To investigate the mechanism by which RA and arsenic trioxide induce remission in APL.
- To determine whether LIC clearance or cellular differentiation is the primary driver of APL cure.
- To explore the potential of oncogene degradation as a therapeutic strategy for APL and other cancers.
Main Methods:
- Utilized murine models of APL and ex vivo/in vivo patient samples.
- Assessed the effects of RA and arsenic trioxide on PML/RARA protein stability and transcriptional repression.
- Investigated the impact of these agents on promyelocyte differentiation and LIC clearance.
- Examined the synergistic effects of RA and arsenic trioxide on PML/RARA degradation and LIC clearance.
Main Results:
- RA and arsenic trioxide induce differentiation and LIC clearance, but these processes can be uncoupled.
- Suboptimal RA concentrations or PLZF/RARA variants lead to differentiation without LIC clearance or remission.
- The combination of RA and arsenic trioxide synergistically degrades PML/RARA via proteasome-dependent mechanisms.
- This synergistic degradation rapidly clears LICs, leading to APL eradication in preclinical models and patients.
Conclusions:
- LIC clearance, mirroring PML/RARA degradation, is the principal mechanism for APL cure with RA/arsenic trioxide therapy.
- Differentiation alone is insufficient for achieving complete disease remission.
- Targeted oncogene degradation represents a potentially broadly applicable therapeutic strategy for eliminating LICs in various malignancies.
