Xq24/IL13RA1 aberrations as key drivers of female bias in primary mediastinal large B-cell lymphoma

Abstract

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 hXIST RNA-fluorescence in situ hybridization (FISH) in two PMBCL-derived cell lines. Further transcriptomic analysis revealed IL13RA1 (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 IL13RA1 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/IL13RA1 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/IL13RA1 defects by female-exclusive genetic/epigenetic mechanisms (CN-LOHX and reactivation of IL13RA1 on Xi) not operating in males.