Abstract
Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrantinteraction among PML/RARA, nucleophosmin (NPM), and topoisomerase II beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML); therefore, our model may be applicable to other more common leukemias driven by NPM.
Highlights
Nuclear receptors are ligand-activated transcription factors that transduce messages carried by signaling molecules into transcriptional responses
We previously reported that retinoic acid (RA)-resistance in the MR2 cell line, which retains wild-type PML/RARA, is associated with an altered pattern of high-molecular weight complexes binding to PML/ RARA (Rosenauer et al, 1996)
Levels of PML/RARA-Interacting Proteins Are Elevated in the MR2 Resistant Line Previous work using high-performance liquid chromatography (HPLC) analysis of PML/RARA in the RA-resistant MR2 line revealed the formation of higher molecular-weight PML/RARA complexes, not evident in the parental NB4 line (Rosenauer et al, 1996)
Summary
Nuclear receptors are ligand-activated transcription factors that transduce messages carried by signaling molecules into transcriptional responses. The retinoid receptor alpha (RARA) finely tunes granulocytic differentiation by acting as a transcriptional regulator of genes involved in this program (Kastner et al, 2001). RARA undergoes a conformational change, releasing co-repressors, and recruiting an arsenal of co-activator proteins that facilitate the recruitment of RNA polymerase II (RNAPII) and the general transcription factors (GTFs) to the promoter (Dilworth and Chambon, 2001; Shao et al, 2000). BRG1, the ATPase subunit of the SWI/SNF complex, plays a critical role in differentiation through regulation of gene expression and is required for transactivation by many nuclear receptors, including RARA (Dilworth et al, 2000)
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