Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain.
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
Cancer Res. 2022 Mar 15;82(6):1098-1109. doi: 10.1158/0008-5472.CAN-21-3386.
Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/- mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development.
JAK/STAT inhibition suppresses tumorigenesis in a B-ALL-susceptible mouse model, presenting a novel approach to prevent B-ALL onset.
预防儿童 B 细胞急性淋巴细胞白血病（B-ALL）的发生是一个长期存在且尚未解决的挑战。PAX5 基因的杂合性种系改变可导致 B-ALL，当影响 JAK/STAT 信号通路的继发性突变积累时。临床前研究表明，这种恶性转化仅在免疫应激下发生，例如暴露于感染性病原体。在这里，我们在 Pax5+/- 小鼠中表明，临床相关剂量的鲁索替尼（一种 JAK1/2 抑制剂）的短暂、早期生命期给药，可显著减轻感染后发生 B-ALL 的风险；用鲁索替尼治疗的 29 只动物中有 1 只发生了 B-ALL，而未经治疗的 34 只小鼠中有 8 只发生了 B-ALL。鲁索替尼治疗优先靶向 Pax5+/- 与野生型 B 细胞祖细胞，并对 Pax5+/- B 细胞祖细胞转录程序产生独特的影响。这些发现为预防 B-ALL 发展的潜在策略提供了首个体内证据。
JAK/STAT 抑制可抑制易感 B-ALL 小鼠模型中的肿瘤发生，为预防 B-ALL 发病提供了一种新方法。
