Acute promyelocytic leukemia (APL): a review of the literature

Abstract

Acute Promyelocytic Leukemia (APL) is characterized by a block in differentiation where leukemic cells are halted at the promyelocyte stage. A characteristic balanced chromosomal translocation between chromosomes 15 and 17 t (15;17) (q24; q21) is seen in 95% of cases - the translocation results in the formation of the PML-RARA fusion protein. The introduction of retinoic acid (RA) and arsenic trioxide (ATO) has been responsible for initially remarkable cure rates. However, relapsed APL, particularly in the high-risk subset of patients, remains an important clinical problem. In addition, despite the success of ATRA & ATO, many clinicians still elect to use cytotoxic chemotherapy in the treatment of APL. Patients who become resistant to ATO have an increased risk of mortality. The probability of relapse is significantly higher in the high-risk subset of patients undergoing treatment for APL; overall approximately 10-20% of APL patients relapse regardless of their risk stratification. Furthermore, 20-25% of patients undergoing treatment will develop differentiation syndrome, a common side effect of differentiation agents. Recent evidence using in vitro models has shown that mutations in the B2 domain of the PML protein, mediate arsenic resistance. Alternative agents and approaches considering these clinical outcomes are needed to address ATO resistance as well as the relapse rate in high risk APL.

Keywords: arsenic trioxide; promyelocytic leukemia; resistance; retinoic acid.

Figure 1. PML-RARA transcriptional repression.

The presence of the fusion protein interferes with the transcription of retinoic acid response elements and disrupts the formation of nuclear bodies. The fusion protein, in the absence of pharmacological doses of retinoic acid, recruits co-repressors to silence gene transcription related to differentiation and prevents apoptosis. NCOR: nuclear receptor corepressor, SMRT: silencing mediator for retinoid and thyroid hormone receptor, RARE: retinoic acid response elements, RARA: retinoic acid receptor alpha, PML: promyelocytic leukemia protein, HDAC: histone deacetylase.

Figure 2. Model for the mechanism of Arsenic trioxide in APL therapy.

Arsenic trioxide binds to cysteine residues on the PML moiety of PML-RARA, triggering the binding of ubiquitin-conjugating enzyme 9 (UBC9) to the PML RING finger domain. UBC9 recruitment then allows the PML-RARA moiety to undergo sumoylation [19]. The attachment of these ubiquitin-like proteins recruits ring finger protein 4(RNF4) onto PML nuclear bodies [25, 35, 36]. RNF4 is a SUMO-dependent ubiquitin ligase that polyubiquitylates PML, targeting it towards the proteasome for degradation. ATO: arsenic trioxide, RXR: retinoic X receptor, U: ubiquitin molecules, Su: SUMO groups, RNF4: ring finger protein 4.