Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Campus M. de Unamuno s/n, Salamanca, Spain.
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
Nat Commun. 2023 Aug 24;14(1):5159. doi: 10.1038/s41467-023-40961-z.
The initial steps of B-cell acute lymphoblastic leukemia (B-ALL) development usually pass unnoticed in children. Several preclinical studies have shown that exposure to immune stressors triggers the transformation of preleukemic B cells to full-blown B-ALL, but how this takes place is still a longstanding and unsolved challenge. Here we show that dysregulation of innate immunity plays a driving role in the clonal evolution of pre-malignant Pax5 B-cell precursors toward leukemia. Transcriptional profiling reveals that Myd88 is downregulated in immune-stressed pre-malignant B-cell precursors and in leukemic cells. Genetic reduction of Myd88 expression leads to a significant increase in leukemia incidence in Pax5Myd88 mice through an inflammation-dependent mechanism. Early induction of Myd88-independent Toll-like receptor 3 signaling results in a significant delay of leukemia development in Pax5 mice. Altogether, these findings identify a role for innate immunity dysregulation in leukemia, with important implications for understanding and therapeutic targeting of the preleukemic state in children.
B 细胞急性淋巴细胞白血病 (B-ALL) 的初始阶段在儿童中通常不易察觉。几项临床前研究表明，暴露于免疫应激源会触发前白血病 B 细胞向完全成熟的 B-ALL 的转化，但具体过程仍未解决。本研究表明，固有免疫失调在恶性前 Pax5 B 细胞前体向白血病的克隆进化中起驱动作用。转录谱分析显示，Myd88 在免疫应激性恶性前 B 细胞前体和白血病细胞中下调。通过炎症依赖机制，遗传降低 Myd88 表达会导致 Pax5Myd88 小鼠的白血病发病率显著增加。早期诱导 Myd88 非依赖性 Toll 样受体 3 信号会导致 Pax5 小鼠白血病的发生明显延迟。总之，这些发现确定了固有免疫失调在白血病中的作用，对理解和靶向治疗儿童前白血病状态具有重要意义。
