TWIST2 high expression defines a novel subtype of B-cell precursor acute lymphoblastic leukemia

Repository: https://jhuanglab.github.io/twist2/

Principal Investigator: Jhuanglab

Contact: hiekeen [at] gmail.com

This repository supports the study "TWIST2 high expression defines a novel subtype of B-cell precursor acute lymphoblastic leukemia", which identifies and characterizes a rare but distinct molecular subtype of BCP-ALL driven by aberrant overexpression of the transcription factor TWIST2.

Overview

By integrating transcriptomic data from 3,371 BCP-ALL samples across 23 public and in-house datasets, we uncovered a previously unclassified subgroup (0.5%, n=17) with uniformly high TWIST2 expression. This TWIST2-high subtype: - Lacks known canonical fusions (e.g., DUX4, MEF2D, KMT2A) - Shows mutually exclusive mutations in metabolic genes: 7 cases harbor a recurrent germline-associated FH A273T variant, while 4 carry IDH1/2 mutations - Exhibits poor overall survival (<50% at 3 years) - Displays gene expression signatures linked to epithelial-mesenchymal transition (EMT), FGF signaling, and immunosuppression (e.g., CD274/PD-L1 upregulation)

Functional assays confirm that TWIST2 overexpression impairs proliferation in BCP-ALL cell lines and murine pro-B cells by inducing cell cycle arrest—consistent with its context-dependent tumor-suppressive role.

Repository Contents

• Analysis code: Reproducible pipelines for RNA-seq processing, UMAP clustering, mutation calling, and survival analysis
• Data resources: Sample annotations, differential expression results, and mutation tables
• Documentation: Detailed methods aligned with the manuscript

Access

• Code: https://github.com/JhuangLab/twist2

• Interactive site: https://jhuanglab.github.io/twist2

• Data: Available upon request from the corresponding authors