Leukemic mesenchymal stromal cell COX2-PG signaling regulates donor anti-leukemia immunity

Abstract

Hematopoietic stem cell transplantation (HSCT) is considered the gold standard for treatment of hematologic malignancies, including Fanconi anemia (FA), a cancer-prone disease with extremely high incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, eradication of residual leukemia stem cells (LSCs), which often contributes to relapse, remains the challenge for HSCT. Here we investigate the interaction between leukemic mesenchymal niche and donor hematopoietic stem progenitor cells (HSPCs) by modeling FA HSCT. We found that healthy donor CD34+ HSPCs cocultured on mesenchymal stromal cells (MSCs) derived from patients with AML exhibit high human engraftment characteristic of HSPC and myeloid expansion in NOD/SCID/IL-2gamma-/-/SGM3 (NSGS) mice. LC/MS-based untargeted metabolomics analysis revealed that prostaglandins (PGs), an inflammatory component of the mesenchymal secretome, are the only metabolites that are progressively elevated in MDS and AML MSCs compared to the MSCs from healthy donors or patients with cytopenias but without cancer. Inhibition of the inflammatory cyclooxygenase 2 (COX2) in the AML MSCs ex vivo ameliorates HSPC and myeloid expansion in transplanted recipients of the cocultured CD34+ cells. In addition, transcriptome analysis demonstrated dysregulation of genes involved in the NR4A family of nuclear hormone transcription factors (TFs) and the WNT/-catenin signaling pathway in the CD34+ cells co-cultured on MSCs derived from AML patients. Consistently, reduced MSC secretion of PGs subsequent to inhibition of COX2 leads to a significant decrease in the expression of the NR4A TFs and the WNT signaling genes including Wnt ligand WNT5A, -catenin (CTNNB1) and the WNT effector LEF1 in cocultured CD34+ cells. Furthermore, knocking down the NR4A TFs or CTNNB1 abrogated the expansion of progeny of the AML MSC-cocultured HSPCs in recipient mice. Together, these findings suggest that specific interactions between leukemic mesenchymal niche and donor HSPCs orchestrate a novel COX2/PG/NR4A signaling axis, connecting inflammation, cellular metabolism and cancer immunity.