B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common childhood cancer, originates from lymphoid precursor cells in bone marrow committed to the B-cell lineage. Environmental factors and genetic abnormalities disturb the normal maturation of these precursor cells, promoting the formation of leukemia cells and suppressing normal hematopoiesis. The underlying mechanisms of progression are unclear, but BCP-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. This study hypothesized that air pollution and haze are risk factors for BCP-ALL progression. The current study revealed that indeno(1,2,3-cd)pyrene (IP), a major component of polycyclic aromatic hydrocarbons (PAHs) in air, promotes oncogenic activities (proliferation, transformation, and disease relapse) in vitro and in vivo. Mechanistically, IP treatment activated the aryl hydrocarbon receptor (AHR)–indoleamine-2,3-dioxygenase (IDOs) axis, thereby enhancing tryptophan metabolism and kynurenine (KYN) level and consequent promoting the KYN–AHR feedback loop. IP treatment decreased the time to disease relapse and increased the BCP-ALL cell count in an orthotopic xenograft mouse model. Additionally, in 50 clinical BCP-ALL samples, AHR and IDO were co-expressed in a disease-specific manner at mRNA and protein levels, while their mRNA levels showed a significant correlation with disease-free survival duration. These results indicated that PAH/IP exposure promotes BCP-ALL disease progression.

Graphical abstract

中文翻译：

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芳基烃受体-犬尿氨酸轴促进 BCP-ALL 的致癌活性

B 细胞前体急性淋巴细胞白血病 (BCP-ALL) 是最常见的儿童癌症，起源于骨髓中属于 B 细胞谱系的淋巴前体细胞。环境因素和遗传异常扰乱这些前体细胞的正常成熟，促进白血病细胞的形成并抑制正常造血。潜在的进展机制尚不清楚，但 BCP-ALL 的发病率似乎随着现代生活方式的采用而增加。本研究假设空气污染和雾霾是 BCP-ALL 进展的危险因素。目前的研究表明，茚并（1,2,3-cd）芘（IP）是空气中多环芳烃（PAH）的主要成分，在体外和体内促进致癌活动（增殖、转化和疾病复发） 。从机制上讲，IP治疗激活芳基碳氢化合物受体（AHR）-吲哚胺-2,3-双加氧酶（IDO）轴，从而增强色氨酸代谢和犬尿氨酸（KYN）水平，从而促进KYN-AHR反馈回路。在原位异种移植小鼠模型中，IP 治疗可缩短疾病复发时间并增加 BCP-ALL 细胞计数。此外，在50个临床BCP-ALL样本中，AHR和IDO在mRNA和蛋白质水平上以疾病特异性方式共表达，而它们的mRNA水平与无病生存时间显着相关。这些结果表明 PAH/IP 暴露促进 BCP-ALL 疾病进展。

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