Deep Proteomic Analysis reveals Significant Similarities Between Cancer-Associated and Familial Hemophagocytic Lymphohistiocytosis
2Division of Immunobiology, Cincinnati Children's Hospital Medical Center, USA
3Sackler School of Medicine, Tel Aviv University, Israel
4Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Israel
5Internal Medicine "D", Sheba Medical Center, Israel
6Division of Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Israel
7Hematology Institute, Sheba Medical Center, Israel
8Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, USA
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome increasingly recognized in patients with hematologic malignancies (HM-HLH). Diagnosis and treatment of HM-HLH are extrapolated from studies in familial HLH (FHL) which occurs in young children and is driven by excessive CD8+ T cell activation and interferon-gamma production. By contrast, little is known regarding the pathophysiology of HM-HLH. We have established a novel set of laboratory criteria termed the `optimized HLH inflammatory (OHI) index,` which improves diagnosis and prognostic estimation in HM patients (Zoref et al. Blood; 2022). Based on our findings, we hypothesized that HM-HLH has similar pathophysiology to FHL. We utilized the SomaLogic proteomics platform to assay 7,596 serum proteins and examined the similarities between syndromes. For unsupervised clustering of patient results, primary component analysis and heatmap analyses were performed. Finally, gene cell enrichment analysis (GSEA) with hallmark pathway determination was performed on each pairwise comparison and the overlapping differential genes. Forty-two patients were studied: 28 HM-OHI+/- patients matched by malignancy type, 7 FHL, and seven age-matched controls, with unsupervised clustering, HM-OHI+ patients clustered with FHL patients, while healthy controls and HM-OHI- patients clustered together. In pairwise comparisons (FHL vs. controls and HM-OHI+ vs. HM-OHI-), 496 differential genes were shared between FHL and HM-OHI+ patients. Furthermore, in a GSEA analysis, interferon-gamma response was significantly enriched in GSEA analysis of the intersecting genes. These data provide strong independent, biological validation for the OHI index as a clinical diagnostic tool for HM-HLH And suggest similar pathophysiology between HM-HLH/ OHI+ and FHL patients.