Targeting TCF3 addiction in multiple myeloma

Description

Multiple myeloma remains an incurable malignancy, with most patients ultimately relapsing due to therapy-resistant disease. While the genetic landscape of multiple myeloma is highly heterogeneous, malignant plasma cells often converge on shared transcriptional dependencies that sustain tumor survival. Among these, the transcription factor TCF3 has emerged as a highly selective and previously unexplored vulnerability in multiple myeloma. We propose to define the transcriptional, signaling, and metabolic programs driven by TCF3 and to develop innovative therapeutic strategies to target this dependency. Our approach combines functional genomics, multi-omic profiling, metabolic targeting, and AI-guided small-molecule discovery to identify novel ways to suppress TCF3 activity in myeloma cells. This work aims to establish TCF3 as a new therapeutically actionable target and generate the preclinical foundation for future translational development in patients with relapsed or refractory multiple myeloma.