Preprint Review Version 1 This version is not peer-reviewed

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

Version 1 : Received: 4 October 2019 / Approved: 14 October 2019 / Online: 14 October 2019 (10:49:36 CEST)

How to cite: Noguera, N.I.; Catalano, G.; Banella, C.; Divona, M.; Faraoni, I.; Ottone, T.; Arcese, W.; Voso, M.T. Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies. Preprints 2019, 2019100159 (doi: 10.20944/preprints201910.0159.v1). Noguera, N.I.; Catalano, G.; Banella, C.; Divona, M.; Faraoni, I.; Ottone, T.; Arcese, W.; Voso, M.T. Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies. Preprints 2019, 2019100159 (doi: 10.20944/preprints201910.0159.v1).

Abstract

In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. 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. Resistance to ATRA and ATO may derive from 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 induction of apoptosis in APL cells.

Subject Areas

APL; Therapy; NGS; Resistance; ATO; ATRA; Ascorbate

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.