Friday, May 9, 2025
5/9/2025
Hodgkin’s Lymphoma-induced Nephrotic Syndrome - SUMMARY / ABSTRACT (max 30 lines) Hodgkin Lymphoma (HL) is a malignant condition most prevalent in adolescents and young adults (3 new cases per 100,000 individuals per year). About 0.5 to 1% of HL patients develop nephrotic syndrome (NS). Hodgkin Reed–Sternberg (HRS) cells, representing about 1% of the tumor bulk, release cytokines and soluble proteins into the circulation that may reach the kidney where they trigger the development of NS. Published evidence in literature shows the presence of a ZHX2 hypomorph (ZHX2hypo/hypo) state in the tumor in HL, and several HRS cell lines are also known to have a ZHX2hypo/hypo state. The PI recently showed that Rhinovirus cytokine storm cocktails, a model for common cold induced MCD relapse, induce glomerular injury and albuminuria selectively in ZHX2hypo/hypo BALB/cJ and Zhx2flox/flox; NPHS2 promoter cre+/+ mice. The PI showed that the ZHX2hypo/hypo state is a key genomic defect in Minimal Change Disease (MCD) and some Focal Segmental Glomerulosclerosis (FSGS) patients. Preliminary data generated by the PI show a ZHX2hypo/hypo state and the presence of the same insertion at Chr8: 122,533,694 in the L-1236 HRS cell line and in some patients with HL that develop NS. When this insertion found in HL patients is replicated in cultured human podocytes using CRISPR/Cas9 editing, it triggers a ZHX2hypo/hypo state. When cytokines and soluble proteins present in the supernatant of the L-1236 HL cell line are injected into ZHX2hypo/hypo state and control mice, they trigger development of albuminuria only in ZHX2hypo/hypo state mice. The PI generated a cytokine HL cocktail replicating the secreted cytokine and soluble proteins profile of L-1236 cells and successfully induced albuminuria only in ZHX2hypo/hypo state mice. The PI identified the threshold nephritogenic dose 1X of the HL cocktail that induces significant histological glomerular injury and albuminuria in ZHX2hypo/hypo state mice. Hypothesis: A combination of cytokines and soluble proteins released by HRS cells induce glomerular injury and albuminuria in ZHX2hypo/hypo mice to mimic HL related NS. Depleting selected cytokines or soluble proteins alone or in combination, with antibodies, will improve glomerular injury and albuminuria in HL. In Specific Aim 1, injection of HL cell supernatant or HL cytokine cocktail to replicate the phenomenon of HL- induced glomerular injury and albuminuria in ZHX2hypo/hypo mice. Cell signaling in CRISPR-edited ZHX2hypo/hypo human podocytes will be studied. The contribution of IL-4Rα and other identified major components of the cocktail will be investigated. In Specific Aim 2, xenotransplant of HRS cells into immunodeficient NSG mice in a ZHX2hypo/hypo background to develop a new rodent model of HL and study the development of NS. In Specific Aim 3, treatment of HL-related glomerular injury and albuminuria by anti-cytokines antibodies (single or in combination) or their receptors blockage (alternative strategy) will be assessed for therapeutic response in ZHX2hypo/hypo BALB/cJ mice injected with HL cocktail and the new tumor HL mice model.
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