Retinoic acid regulatory pathways, chromosomal translocations, and acute promyelocytic leukemia

Abstract

Retinoic acids (RAs) exert a broad range of physiologic actions during embryonic development and adult life. Two families of RA receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), have been identified. The therapeutic effect of all‐trans‐RA (ATRA) in induction of remission for acute promyelocytic leukemia (APL) has largely been proved, and this has, over the past 10 years, greatly stimulated research on oncogenesis and RA‐regulated differentiation pathways. In APL, one of the RAR genes, RARA, is fused to PML in the great majority of patients as a result of the chromosomal translocation t(15;17). However, a small subset of APL patients have a different fusion gene, PLZF‐RARA, resulting from the variant translocation t(11;17). A third translocation, t(5;17), in which the NPM gene is fused to RARA, has been described. Current data suggest that PML‐RARα and PLZF‐RARα fusion receptors may play an important role in the development of APL and that PML‐RARα could be the target of ATRA differentiation therapy. Characterization of the genes regulated by retinoic acid may open up new prospects for an understanding of the mechanisms of ATRA differentiation therapy for APL and may help to extend the concept of cancer‐targeting treatment to other types of leukemias or solid tumors. Genes Chromosom Cancer 15:147–156 (1996). © 1996 Wiley‐Liss, Inc.

Myb binding proteins: regulators and cohorts in transformation

“…Dominant-negative versions of RARa can block the di erentiation of hematopoietic cell lines in tissue culture and in vivo. For example, myeloid (Ying et al, 1997) leukemias result from the transforming potential of the dominant-negative Pml-RARa fusion protein (for reviews see Chen et al, 1996;Grignani et al, 1993). Thus, the e ect of RARa is opposite to that of cMyb, and recent evidence suggests that expression of RARa may inhibit the activity of c-Myb and v-Myb in hematopoietic cells (P®tzner et al, 1998).…”

Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways

“…1 Five different chromosomal translocations have been reported and characterized so far in acute promyelocytic leukemia (APL), a disease effectively treated by agents that target the resultant chimeric transcription factor. [2][3][4] In the great majority of patients, there is a specific chromosomal translocation t(15;17)(q22;q21), which involves the PML (promyelocytic leukemia) gene located on chromosome 15 and the RARA (retinoic acid receptor ␣) gene located on chromosome 17. 5,6 The wild-type PML is a component of a nuclear structure referred to as PML nuclear body or POD (PML oncogenic domain).…”

Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF–RAR α and NPM–RAR α

“…These chromosomal translocations invariably involve the RAR␣ (retinoic acid receptor ␣) gene on chromosome 17, and the PML (promyelocytic leukemia), PLZF (promyelocytic leukemia zinc finger), NPM (nucleophosmin), and NuMA (nuclear mitotic apparatus protein) genes on chromosomes 15q22, 11q23, 5q32, and 11q13, respectively (3)(4)(5)(6)(7)(8)(9)(10). The breakpoints in the RAR␣ gene are always fixed, regardless of its fusion partner; therefore, RAR␣ retains the same functional domains (B-F), including the DNA, corepressor͞coactivator, and ligand binding regions in all fusion proteins (11,12). RARs are transcription factors that bind to RAREs (retinoic acid response elements) in a heterodimer formed with RXRs (retinoic X receptors; refs.…”