T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液恶性肿瘤，与难治性/复发性疾病相关的悲观预后，需要新的靶向治疗。IL7受体途径基因（IL7Rp）的激活突变在T-ALL中扮演确认的白血病支持角色。JAK抑制剂如瑞托尼布最近展示了临床前的功效。然而，缺乏JAK抑制剂的敏感性预测标记。在此，我们展示IL7R（CD127）表达在T-ALL（约70%）中比IL7Rp突变（约30%）更频繁。我们比较了所谓的非表达者（无IL7R表达/IL7Rp突变），表达者（有IL7R表达但没有IL7Rp突变）和突变体（有IL7Rp突变）。综合多组学分析描绘出IL7R不健康状态在事实上所有T-ALL亚型中，在非表达者的表观遗传水平，在突变体的基因水平，在表达者的转录后水平。基于原代移植物外数据的结果，支持了当表达IL7R时，IL7Rp是功能性的，无论IL7Rp的突变状态如何。因此，瑞托尼布在表达者和突变体中均抑制T-ALL的存活。有趣的是，我们发现表达者表现出异位IL7R表达和IL7Rp上瘾，赋予更深的瑞托尼布敏感性。相反，突变体对维内托拉克斯比表达者更敏感。总体而言，瑞托尼布和维内托拉克斯的联合使用在两个群体中显示出协同效应。我们通过报道两名难治性/复发性T-ALL患者达到完全缓解来说明此联合治疗的临床相关性，这为将此策略用作移植前的桥梁提供了概念证明。总之，IL7R表达可以用作JAK抑制剂的敏感性生物标志物，从而将T-ALL患者的低敏感性扩展到接近T-ALL的70％。版权©2023年美国血液学会。

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.Copyright © 2023 American Society of Hematology.