# Targeting the Liquid–Liquid Separation Region of c‐Maf for Treating Chromosomal Translocations in Multiple Myeloma

## TL;DR

This study shows that targeting the phase separation of c-Maf can inhibit the progression of multiple myeloma driven by chromosomal translocations.

## Contribution

A new therapeutic strategy is proposed by targeting the phase separation mechanism of the transcription factor c-Maf in multiple myeloma.

## Key findings

- Elevated c-Maf promotes MM progression through liquid–liquid phase separation (LLPS).
- Benzoyl benzoic acid (BBA) inhibits c-Maf's LLPS, blocking RNA Pol II recruitment and Mtbp transcriptional activation.
- Targeting c-Maf's LLPS successfully inhibits c-Myc-driven MM progression in experimental models.

## Abstract

Multiple myeloma (MM), as an incurable hematologic malignancy, is driven by chromosomal translocations. Recent research suggests that targeting phase separation may offer a new therapeutic vulnerability for MM. The transcription factor c‐Maf is implicated in MM‐associated translocations and undergoes liquid–liquid phase separation (LLPS). Although c‐Maf is historically classified as “undruggable” for its transcription factor nature, we propose a new therapeutic strategy targeting its phase separation mechanism. Comprehensive in vitro and in vivo experiments indicated that elevated c‐Maf promoted MM progression through LLPS. Mechanistically, the alanine‐rich intrinsically disordered regions (IDRs) in c‐Maf drive hydrophobic interactions, enabling phase separation. These IDRs recruit RNA Polymerase II (RNA Pol II) through similar interactions, forming oncogenic condensates that activate the Mtbp/c‐Myc axis. Notably, we discovered benzoyl benzoic acid (BBA) as a candidate compound targeting the inter‐IDR interaction domain of c‐Maf. BBA binding impedes c‐Maf's LLPS capacity, consequently blocking RNA Pol II recruitment and Mtbp transcriptional activation. This mechanistic interference successfully inhibited c‐Myc‐driven MM progression in experimental models. Our study demonstrates that c‐Maf‐driven LLPS activates the c‐Maf/RNA Pol II/Mtbp/c‐Myc axis, highlighting phase separation targeting as a promising therapeutic strategy for translocation‐associated MM patients.

Targeting the liquid‐liquid separation region of c‐Maf for treating pathogenic chromosomal translocations in multiple myeloma. c‐Maf promotes cell proliferation by forming liquid–liquid phase separation (LLPS) to recruit RNA Pol II and activate the Mtbp/c‐Myc axis in multiple myeloma (MM), while targeting the LLPS region of c‐Maf impedes the progression of MM.