# Combinatorial BCL2/BCL2L1 expression predicts clinical response to ruxolitinib in myelofibrosis

## TL;DR

High baseline expression of BCL2 and BCL2L1 genes predicts better response to ruxolitinib in myelofibrosis patients.

## Contribution

A combinatorial score of BCL2 and BCL2L1 gene expression improves prediction of ruxolitinib response in myelofibrosis.

## Key findings

- Baseline BCL2 and BCL2L1 expression is significantly higher in responders to ruxolitinib.
- A combinatorial score of BCL2 and BCL2L1 outperforms individual genes in predicting treatment response.
- Responders show BCL2 down-regulation when treatment response is lost.

## Abstract

Myelofibrosis is characterized by aberrant JAK/STAT signaling, with approved therapy including the JAK inhibitor ruxolitinib. Preclinical evidence implicates BCL-2 family proteins in MF pathogenesis and therapeutic response. Here, we evaluated baseline and on-treatment expression of BCL2, BCL2L1 (encoding BCL-xL), and MCL1 in 19 myelofibrosis patients receiving ruxolitinib. Quantitative PCR fold-change (FC) values, relative to healthy donors, revealed reduced baseline BCL2 (mean FC 0.15) and MCL1 (0.32) expression, with BCL2L1 showing a non-significant trend toward upregulation. Baseline BCL2 and BCL2L1 expression was significantly higher in patients achieving spleen response (responders; n = 7) compared to non-responders (BCL2: 0.30 vs 0.07, p = 0.0130; BCL2L1: 2.73 vs 0.52, p = 0.0096). Logistic regression confirmed both as independent predictors of response. We derived a combinatorial score (CS = FCBCL-2 * FCBCL2L1), which outperformed individual genes in response prediction, as confirmed in logistic regression analysis (OR, 7.5; p = 0.0028). ROC-defined cutoff (0.06) stratified patients by likelihood of response (OR 3.3, p = 0.0037). Longitudinal analysis showed no significant overall change in gene expression on ruxolitinib, but responders exhibited BCL2 down-regulation at loss of response (p = 0.0419). Overall, these preliminary findings suggest that BCL2 and BCL2L1 expression, individually and via a simple CS, predict response to ruxolitinib in myelofibrosis. While limited by small sample size and retrospective design, our data support prospective validation and exploration of BCL-2 pathway modulation as a therapeutic strategy.

The online version contains supplementary material available at 10.1186/s40364-025-00865-0.