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<p>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 <i>BCL2</i>, <i>BCL2L1</i> (encoding BCL-xL), and <i>MCL1</i> in 19 myelofibrosis patients receiving ruxolitinib. Quantitative PCR fold-change (FC) values, relative to healthy donors, revealed reduced baseline <i>BCL2</i> (mean FC 0.15) and <i>MCL1</i> (0.32) expression, with <i>BCL2L1</i> showing a non-significant trend toward upregulation. Baseline <i>BCL2</i> and <i>BCL2L1</i> expression was significantly higher in patients achieving spleen response (responders; <i>n</i> = 7) compared to non-responders (<i>BCL2</i>: 0.30 vs 0.07, <i>p</i> = 0.0130; <i>BCL2L1</i>: 2.73 vs 0.52, <i>p</i> = 0.0096). Logistic regression confirmed both as independent predictors of response. We derived a combinatorial score (CS = FC<sup><i>BCL-2</i></sup> * FC<sup><i>BCL2L1</i></sup>), which outperformed individual genes in response prediction, as confirmed in logistic regression analysis (OR, 7.5; <i>p</i> = 0.0028). ROC-defined cutoff (0.06) stratified patients by likelihood of response (OR 3.3, <i>p</i> = 0.0037). Longitudinal analysis showed no significant overall change in gene expression on ruxolitinib, but responders exhibited BCL2 down-regulation at loss of response (<i>p</i> = 0.0419). Overall, these preliminary findings suggest that <i>BCL2</i> and<i> BCL2L1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • Giacomo Coltro,
  • Viola Videschi,
  • Francesca Gesullo,
  • Federica Violi,
  • Manjola Balliu,
  • Alessandro M. Vannucchi,
  • Paola Guglielmelli

摘要

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.