Inhibition of Inflammatory Signaling in Pax5 Mutant Cells Mitigates B-cell leukemogenesis against leukemia. Inhibition of Inflammatory Signaling in Pax5 Mutant Cells Mitigates B-cell leukemogenesis against leukemia

We used microarrays to investigate gene expression changes in healthy and leukemic cells from Pax5+/- and IL6+/-;Pax5+/- mice in CF and SPF housing conditions. PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers can be detected in neonatal blood spot samples of children who later developed B-cell precursor B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 loss results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. In vivo genetic downregulation of IL-6 in Pax5 mutant mice retards B-cell leukemogenesis. In vivo pharmacologic inhibition of IL-6 with a neutralizing IL-6 antibody in Pax5 mutant mice with B-ALL clears leukemic cells. This exciting novel IL 6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss. Overall design: We used microarrays to investigate gene expression changes in healthy and leukemic cells from Pax5+/- and IL6+/-;Pax5+/- mice in CF and SPF housing conditions.

本研究采用基因芯片（microarray）技术，探究了清洁级饲养环境（Clean Facility, CF）与无特定病原体饲养环境（Specific Pathogen Free, SPF）下，Pax5杂合子小鼠（Pax5+/-）及IL6与Pax5双杂合子小鼠（IL6+/-;Pax5+/-）的健康细胞与白血病细胞中的基因表达变化。PAX5是B细胞急性淋巴细胞白血病（B-cell acute lymphoblastic leukemia, B-ALL）中最常发生突变的基因之一，携带遗传性白血病前期PAX5突变的儿童罹患该病的风险显著升高。后续罹患前体B细胞急性淋巴细胞白血病（B-cell precursor B-ALL）的儿童，其新生儿干血斑样本中可检测到炎症标志物表达异常谱。然而，炎症信号如何促进B-ALL的发生发展仍不明确。本研究证实，Pax5缺失会导致炎症细胞因子白细胞介素6（interleukin-6, IL-6）的生成增强，且IL-6似乎以自分泌方式促进白血病增殖。在Pax5突变小鼠体内通过基因手段下调IL-6的表达，可延缓B细胞白血病的发生进程；在携带B-ALL的Pax5突变小鼠中，使用IL-6中和抗体对IL-6进行药物抑制，可清除体内白血病细胞。本研究在小鼠中发现的这一全新IL-6信号传导范式，在人类样本中也得到了证实。综上，本研究确立了Pax5缺失导致的IL6异常表达作为Pax5依赖性B-ALL的标志性特征，同时将IL-6作为PAX5缺失型B-ALL的治疗易感靶点。实验整体设计：本研究采用基因芯片技术，探究了清洁级饲养环境与无特定病原体饲养环境下，Pax5杂合子小鼠及IL6与Pax5双杂合子小鼠的健康细胞与白血病细胞中的基因表达变化。