# BPTF-665aa mediate chromatin remodeling drives chemoresistance in T-LBL/ALL

## TL;DR

This study shows that BPTF-665aa, a protein from a circular RNA, helps T-LBL/ALL cancer cells resist chemotherapy by changing chromatin structure and suggests a new treatment target.

## Contribution

BPTF-665aa is identified as a novel circRNA-derived protein that drives chemoresistance through chromatin remodeling in T-LBL/ALL.

## Key findings

- BPTF-665aa prevents ubiquitination of full-length BPTF and promotes chromatin accessibility at key promoters like c-Myc P2.
- HY-B0509 is a small-molecule inhibitor that binds to BPTF-665aa's active site, offering a potential therapeutic strategy.
- BPTF-665aa's PHD finger and Bromodomain are essential for its chromatin remodeling function.

## Abstract

Chemoresistance remains a major challenge in addressing T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL), underscoring the necessity for novel strategies to unravel the molecular factors driving resistance. Through transcriptomic profiling, circBPTF was found to be markedly overexpressed in chemoresistant samples. Further functional experiments demonstrated that BPTF-665aa, the protein product of circBPTF, plays a pivotal role in mediating resistance. Notably, BPTF-665aa prevents the ubiquitination degradation of full-length BPTF, and promotes chromatin accessibility at key promoter sites, such as that of c-Myc promter 2 (P2), facilitating transcriptional activation crucial for cellular survival and proliferation under therapeutic stress. Structural studies confirmed the motifs of BPTF-665aa, including the Plant Homeodomain (PHD) finger and Bromodomain, essential for its chromatin remodeling function. HY-B0509 was identified as a small-molecule inhibitor of BPTF-665aa, with molecular docking and dynamics simulations showing stable binding to critical residues within the protein’s active site. Overall, this study introduces a new mechanism where circBPTF affects chromatin accessibility, causing chemoresistance, making BPTF-665aa as a potential therapeutic target for treating T-LBL/ALLs.

The online version contains supplementary material available at 10.1186/s13046-025-03556-8.

This study identifies BPTF-665aa, a protein translated from circBPTF, as a key regulator of chromatin accessibility in T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL). BPTF-665aa promotes chromatin remodeling at oncogenic loci, including the c-Myc promoter, facilitating transcriptional activation of resistance-associated genes. Furthermore, we identify a small molecule inhibitor targeting BPTF-665aa, highlighting its potential as a therapeutic strategy. These findings establish a new paradigm linking circRNA-derived proteins and chromatin architecture, positioning BPTF-665aa as a promising therapeutic target.

The online version contains supplementary material available at 10.1186/s13046-025-03556-8.