遗传异质性和同时发生的驱动突变会影响血癌的临床结果，但预测影响多个复杂且相互作用的信号网络的同时发生的突变的新兴影响具有挑战性。在这里，我们使用数学模型来预测同时发生的突变对弥漫性大 B 细胞淋巴瘤和多发性骨髓瘤中细胞信号传导和细胞命运的影响。模拟预测，当突变组合诱导抗凋亡（AA）和促增殖（PP）信号传导时，会对临床预后产生不利影响。我们将患者特异性突变谱整合到个性化淋巴瘤模型中，并确定了所有基因组和细胞源分类中抗凋亡和促增殖 (AAPP) 信号同时上调的患者（8-25% 的患者）。在一个发现队列和两个验证队列中，两种信号状态均不上调、一种（AA 或 PP）或两种（AAPP）信号状态上调的患者分别具有良好、中等和不良的预后。将 AAPP 信号传导与遗传或临床预后预测因素相结合，可以将患者可靠地分为不同的预后类别。预后不良基因簇中的 AAPP 患者的中位总生存期为 7.8 个月，而在验证队列中，缺乏这两种特征的患者在 120 个月时的总生存率为 90%。个性化计算模型能够识别新的风险分层患者亚组，为未来的风险适应临床试验提供有价值的工具。© 2024。作者。

Genetic heterogeneity and co-occurring driver mutations impact clinical outcomes in blood cancers, but predicting the emergent effect of co-occurring mutations that impact multiple complex and interacting signalling networks is challenging. Here, we used mathematical models to predict the impact of co-occurring mutations on cellular signalling and cell fates in diffuse large B cell lymphoma and multiple myeloma. Simulations predicted adverse impact on clinical prognosis when combinations of mutations induced both anti-apoptotic (AA) and pro-proliferative (PP) signalling. We integrated patient-specific mutational profiles into personalised lymphoma models, and identified patients characterised by simultaneous upregulation of anti-apoptotic and pro-proliferative (AAPP) signalling in all genomic and cell-of-origin classifications (8-25% of patients). In a discovery cohort and two validation cohorts, patients with upregulation of neither, one (AA or PP), or both (AAPP) signalling states had good, intermediate and poor prognosis respectively. Combining AAPP signalling with genetic or clinical prognostic predictors reliably stratified patients into striking prognostic categories. AAPP patients in poor prognosis genetic clusters had 7.8 months median overall survival, while patients lacking both features had 90% overall survival at 120 months in a validation cohort. Personalised computational models enable identification of novel risk-stratified patient subgroups, providing a valuable tool for future risk-adapted clinical trials.© 2024. The Author(s).