Marcelis Lukas, Allsop Ryan Nicolaas, Vanden Bempt Marlies, Debackere Koen, Renard Félicien, Tuveri Stefania, Dierickx Daan, Janiszewski Adrian, Balaton Bradley Philip, Vets Johanna, Dewaele Barbara, Michaux Lucienne, Vandenberghe Peter, Cools Jan, Vermeesch Joris Robert, Tousseyn Thomas, Pasque Vincent, Wlodarska Iwona
Translational Cell and Tissue Research KU Leuven Leuven Belgium.
Department of Pathology University Hospitals Leuven Leuven Belgium.
Hemasphere. 2025 Sep 27;9(9):e70200. doi: 10.1002/hem3.70200. eCollection 2025 Sep.
Female-biased incidence in primary mediastinal large B-cell lymphoma (PMBCL) is enigmatic and points to a potential contribution of the X chromosome in this disease. To elucidate the postulated involvement of X-linked factor(s), we profiled the X chromosome in 48 diagnostic PMBCLs of male (21) and female (27) origin. Molecular cytogenetic analysis detected copy number gain of X/Xq in all male patients and 59.3% (16/27) of female patients. The remaining female cases revealed either a cytogenetically cryptic copy-neutral loss of heterozygosity (CNLOH) of X/Xq (14.8%) or germline XX (25.9%). Remarkably, RNAseq data of 28 cases indicated a nonrandom involvement of transcriptionally active X homolog in gain/CNLOH, validated by XIST RNA-fluorescence in situ hybridization (FISH) in two PMBCL-derived cell lines. Further transcriptomic analysis revealed (Xq24) as the target of the Xq aberrations. In agreement with this, the vast majority (32/38, 84.2%) of PMBCL cases were IL13RA1-positive by immunohistochemistry. The intriguing finding of IL13RA1 protein expression in female PMBCLs with germline XX suggests epigenetic reactivation and expression of on the inactive X. Functional in vitro studies performed on Ba/F3 cells showed that overexpressed IL13RA1 is potent to transform murine pro-B cells and constitutively activate the oncogenic JAK-STAT signaling pathway. The novel pathogenic Xq24/ defects appeared as disease-defining aberrations driving PMBCL and contributing to the related sex disparity. Our findings indicate that female predominance in PMBCL is due to the higher risk of women of acquiring pathogenic Xq24/ defects by female-exclusive genetic/epigenetic mechanisms (CN-LOHX and reactivation of on Xi) not operating in males.
原发性纵隔大B细胞淋巴瘤（PMBCL）中女性发病率偏高这一现象令人费解，提示X染色体在该疾病中可能发挥作用。为阐明假定的X连锁因子的作用，我们对48例诊断为PMBCL的患者（男性21例，女性27例）的X染色体进行了分析。分子细胞遗传学分析发现，所有男性患者以及59.3%（16/27）的女性患者存在X/Xq拷贝数增加。其余女性病例显示，要么存在X/Xq细胞遗传学隐匿性拷贝中性杂合性缺失（CNLOH）（14.8%），要么为种系XX（25.9%）。值得注意的是，28例病例的RNAseq数据表明，转录活性X同源物在拷贝数增加/CNLOH中存在非随机参与，这在两个PMBCL来源的细胞系中通过XIST RNA荧光原位杂交（FISH）得到了验证。进一步的转录组分析显示（Xq24）是Xq畸变的靶点。与此一致的是，绝大多数（32/38，84.2%）PMBCL病例免疫组化显示IL13RA1呈阳性。在种系XX的女性PMBCL中发现IL13RA1蛋白表达，这一有趣的发现提示了失活X上的表观遗传重新激活和表达。在Ba/F3细胞上进行的体外功能研究表明，过表达的IL13RA1能够有效地转化小鼠前B细胞并持续激活致癌的JAK-STAT信号通路。新发现的致病性Xq24/缺陷表现为界定疾病的畸变，驱动PMBCL并导致相关的性别差异。我们的研究结果表明，PMBCL中女性占优势是由于女性通过男性不存在的女性特有的遗传/表观遗传机制（CN-LOHX和Xi上的重新激活）获得致病性Xq24/缺陷的风险更高。
