Title:

Identifying Novel GLI2-Associated Secretory Targets in Waldenström's Macroglobulinemia

Waldenström's macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by overproduction of monoclonal IgM. WM cells exist along the B-lymphocyte to plasma cell (PC) differentiation spectrum, and inhibition of the Hedgehog transcription factor GLI2 decreases IgM secretion in the WM cell line MWCL-1. Since GLI2 does not regulate IgM via heavy chain gene (IGHM) transcription, we used bioinformatics to identify alternative GLI2-associated secretory targets. Using the GSE6691 microarray, GO enrichment analysis of WM B-lymphocyte to PC differentiation revealed up-regulated genes enriched in secretory processes compared to healthy controls. Pearson correlation showed GLI2 was 1.57x more likely to correlate with secretory machinery genes than immunological genes in WM plasma cells. Candidates (ERN1, STX5, STIM1) were selected based on GLI2 correlation and GLI2 binding motifs in promoter-proximal regions from ATAC-seq. MWCL-1 cells treated with GANT61 (20µM) showed no significant expression changes by qPCR, though IGHM remained unchanged as predicted. Future work will optimize qPCR and leverage a WM scRNA-seq/scATAC-seq dataset (GSE296167) for more robust, cell-resolved analysis.

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