Prostaglandin E 2 signaling promotes adverse survival outcome in B-cell acute lymphoblastic leukemia

Obesity increases risk and worsens treatment outcome of acute lymphoblastic leukemia (ALL). To explore how adipose tissue may contribute to these effects, we previously performed single cell RNA sequencing in obese mice to compare gene expression in ALL from adipose tissue to ALL from marrow. We identified 577 differentially expressed genes (DEGs) with a log 2 -fold threshold of ±0.25 and Bonferroni corrected p-values <0.05. Using ex-vivo coculture of ALL and human adipose explants, we confirmed that adipose tissue upregulates a top DEG, TNFSF11 , in ALL cells via secretion of prostaglandin E2 (PGE 2 ). Additionally, we observed that PGE 2 conferred modest resistance in vitro to vincristine and daunorubicin chemotherapies. In the present study, we explored whether adipose tissue PGE 2 might contribute to poor ALL treatment outcome. We identified six additional genes in the top 50 DEGs that may be induced by PGE 2 -cAMP signaling and confirmed that these genes were upregulated in vitro by 200 ng/mL PGE 2 in BV173 and RS4;11 ALL cell lines (Table)(N=6). To investigate the relevance of these genes to ALL survival, we analyzed data from the TARGET-ALL P2 clinical trial using the NCI GDC Data Portal. TARGET-ALL P2 included pediatric and young adult B-precursor ALL patients treated on Children's Oncology Group protocols, enriched for patients who experienced relapse within 4 years of diagnosis. Survival and RNAseq expression on diagnostic specimens were available for 466 subjects. Expression of these six genes, as well as TNFSF11 , was associated with significantly worse survival, with hazard ratios ranging from 1.7 to 3.7 (Table). Overall, our data shows that adipose tissue PGE 2 can upregulate genes that are associated with a worse prognosis in ALL patients. Further work is needed to test whether adipose tissue PGE 2 is a contributing factor for worse ALL outcomes in obese patients. Gene name Symbol Log 2 FC adipose vs. marrow (scRNAseq) Fold change with PGE 2 (qPCR) BV173, RS4;11 p-value BV173, RS4;11 Hazard ratio Log-rank p-value TNF superfamily member 11 TNFSF11 2.195 5.50, 7.34 0.0020, 0.0365 1.731 0.0043 Fos proto-oncogene, AP-1 transcription factor subunit FOS 1.809 2.18, 4.31 0.029, 0.0004 2.025 0.0004 Fos like 2, AP-1 transcription factor subunit FOSL2 1.561 4.8, 7.67 0.0015, 0.0008 2.289 <0.0001 JunB proto-oncogene, AP-1 transcription factor subunit JUNB 2.730 1.70, 1.24 0.034, 0.023 3.523 <0.0001 JunD proto-oncogene, AP-1 transcription factor subunit JUND 1.616 1.51, 1.87 0.076 (n.s.), 0.0017 3.748 <0.0001 Nuclear receptor subfamily 4 group A member 1 NR4A1 2.184 3.07, 6.63 0.016, 0.0008 2.483 <0.0001 Nuclear receptor subfamily 4 group A member 2 NR4A2 1.871 2.41, 8.10 0.0005, 0.0022 3.431 <0.0001