Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

Abstract

This review highlights new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in acute promyelocytic leukemia (APL). Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of RARa target genes and disrupting PML-NBs. The RAR receptors control the homeostasis of tissue growth, modeling and regeneration, and PML-NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. The additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. The treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. The resistance to ATRA and ATO may derive from the mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or the induction of apoptosis in APL cells.

Keywords: APL; ATO; ATRA; NGS; ascorbate; resistance; therapy.

Figure 1

Schematic representation of the molecular mechanisms involved in acute promyelocytic leukemia (APL) pathogenesis. Promyelocytic leukemia / retinoic acid receptor α (PML/RARA) exerts dominant-negative effects on RAR/RXR-dependent transcriptional control through the recruitment of co-repressor complexes (CoR) (top) and PML nuclear bodies assembly (bottom). The direct or indirect regulation of target genes is responsible for the differentiation block, aberrant self-renewal, and impairment of autophagy and apoptosis observed in APL blasts. PML nuclear bodies disruption drives enhanced self-renewal, inhibition of DNA damage response and inhibition of senescence and apoptosis, in part by p53 inactivation.

Figure 2

Mechanism of resistance to arsenic trioxide- all-trans retinoic acid (ATO-ATRA) therapy in APL. The resistance to ATRA and ATO may derive from: (i) genetic mutations resulting in amino acid substitution in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa (ii) deregulated pathways like AKT/mTOR, activators of MAP kinase pathway and/or other epigenetic controllers or additional gene mutations (ei WT1), (iii) FLT3-ITD severely blunts ATRA response, which fails to degrade PML-RARA protein whose persistence in the cells confers the APL phenotype with PML nuclear body disruption and deactivation of P53 signaling. This type of resistance is overcome by ATO (iv) some autophagy regulatory proteins BECN1 and p62/SQSTM1 have been shown to play a pro-survival role during ATRA and ATO treatment, (v) alterations in the redox system. (vi) Metabolic alterations (vii) High expression of multi drug resistant (MDR) proteins, (viii) Microenvironment influences (ix) Presence of X-RARa fusions.