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. 2019 Oct 18;11(10):1591. doi: 10.3390/cancers11101591

Figure 2.

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.