Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

Abstract

Acute promyelocytic leukemia (APL) accounts for 10-15% of newly diagnosed acute myeloid leukemias (AML) and is typically caused by the fusion of promyelocytic leukemia with retinoic acid receptor α (RARA) gene. The prognosis is excellent, thanks to the all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy. A small percentage of APLs (around 2%) is caused by atypical transcripts, most of which involve RARA or other members of retinoic acid receptors (RARB or RARG). The diagnosis of these forms is difficult, and clinical management is still a challenge for the physician due to variable response rates to ATRA and ATO. Herein we review variant APL cases reported in literature, including genetic landscape, incidence of coagulopathy and differentiation syndrome, frequent causes of morbidity and mortality in these patients, sensitivity to ATRA, ATO, and chemotherapy, and outcome. We also focus on non-RAR rearrangements, complex rearrangements (involving more than two chromosomes), and NPM1-mutated AML, an entity that can, in some cases, morphologically mimic APL.

Keywords: APL-like acute myeloid leukemia; atypical rearrangements; complex rearrangements; genetic landscape; variant acute promyelocytic leukemia.

Figure 1

Schematic representations of RARx translocations. Common (A) and rare (B) RARA rearrangements. RARB (C) and RARG (D) rearrangements. The figures were created with Biorender.com. 5′-UTR, 5′-untranslated region; DBD, DNA-binding domain; LBD, ligand-binding domain; CC, coiled coil domain; POZ, BTB/POZ domain; Pro, proline-rich region; Zn, zinc finger domain; SH3, protein–protein interaction domain; SH2, docking domain for phosphorylated tyrosine residues; BBD, BCOR Bcl6-binding domain; ANK, ankyrin repeats; Fip1, FIP1-binding domain for polymerase; LisH, lissencephaly type-1-like homology motif; DDD, dimerization/docking domain of the type I alpha regulatory subunit of cAMP-dependent protein kinase; ND, nucleoplasmin/nucleophosmin domain; LZ, leucine zipper; PHD TF, plant homeodomain finger transcription factor domain; FN3, fibronectin type 3 domain; GLEBS, Gle2/Rae1-binding sequence; GLFG, Gly-Leu-Phe-Gly repeats; R1, I-repeat domains; RRM, RNA recognition motif; R, RING finger domain; B1 and 2, B box.

Figure 2

Diagnostic algorithm in the suspicion of acute promyelocytic leukemia (APL) and APL-like acute myeloid leukemias. In patients with morphologic, immunophenotypic, or clinical features raising a suspicion of APL, the guidelines (15) recommend molecular genotyping, which can confirm APL diagnosis in a few hours. If the PML/RARA rearrangement is absent, RT-PCR for recurrent translocations and for PLZF/RARA rearrangement, together with NPM1 and FLT3 mutation testing, should be performed. In all cases, cytogenetic tests, including FISH, allow the diagnostic assessment for RARX rearrangements in 1 to 2 days, while conventional karyotyping will detect karyotype abnormalities in 5–7 days, as recommended by ELN 2017 (139).