Classic and Variants APLs, as Viewed from a Therapy Response

Abstract

Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of "classic" APL pathogenesis and therapy response.

Keywords: ATO; ATRA; PML; leukemia; retinoic acid signaling; targeted therapy.

Figure 1

Structural organization of PML-RARA and other PML-independent RAR fusions in acute promyelocytic leukemia (APL) cells. Schematic representations of PML (isoform I), RARA and fusion partners of other retinoic acid receptors (RARB and RARG) before and after chromosomal rearrangements. Exons are shown in blue. The frequency of breakpoint cluster regions (Bcr) in APL is indicated in a percentage and fusion points are represented by a red arrow. The RING finger (R), B-boxes (B1 and B2), coiled-coil domain (CC), nuclear signal (nls) and sumo-interactif motif (SIM) in PML are represented by different colored boxes as well as functional domains in RARA: A-B: AF-1 transcriptional domain; C: DNA binding domain (DBD); D: hinge region; E: ligand binding domain (LBD), heterodimerization and AF-2 transactivation domain; F: unknown function.

Figure 2

Schematic representation of the X-RARs fusions identified in APL: (A–C). Functional domains in X-RARA, X-RARB and X-RARG fusions proteins are represented by colored boxes. Exon and fusion points are indicated by a red arrow. Abbreviations: 5’-UTR: 5’ untranslated region; DBD: DNA binding domain; LBD: ligand binding domain; R: RING finger domain; B1 and 2: B box; 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; BB6: Bcl6- binding domain; ANK: ankyrin repeats; F: FIP1 binding domain for polymerase; FN3: fibronectin 3 domain; R1: putative HLH motif; LisH: lissencephaly type-1-like homology motif; PB1: Phox and Bem1 domain; PQ-rich: proline-glutamine-enriched domain; RRM: RNA recognition motif; GLFG: Gly-Leu-Phe-Gly repeats; GLEBS: Gle2/ Rae1-binding sequence.