Date of Award

Spring 2026

Abstract

Waldenström’s Macroglobulinemia (WM) is a rare non-Hodgkin lymphoma characterized by the increased presence of monoclonal IgM circulating in the blood and the infiltration of lymphoplasmacytic cells into the bone marrow. WM cells are heterogeneous, sharing features of both B-lymphocytes and plasma cells while not being able to terminally differentiate. Our labs’ previous work established that inhibiting and knocking down the GLI2 transcription factor effectively reduces IgM secretion in three different WM cell lines. This observed phenotype was discovered to operate through IL-6Rα signaling but whether IgM was regulated transcriptionally was not assessed. GLI2 was initially hypothesized to regulate IgM production through class switch recombination (CSR) machinery, specifically AID. GLI2 inhibition, knockdown, and overexpression were performed in three different WM cell lines. Promoter activity and mRNA levels were analyzed, but all pointed towards the null. Interestingly, IGHM expression was unchanged, which initiated a bioinformatic pivot to investigate post-transcriptional regulation. A patient microarray showed that WM B-lymphocyte to plasma cell differentiation was overwhelmingly enriched for secretory pathways. GLI2 was found to disproportionately correlate with secretory machinery genes over classical immunology genes. Microarray data was overlaid with ATAC-seq to observe open chromatin. A convergent framework was established to identify genes with GLI2 correlation and GLI2 binding motifs in promoter/enhancer open chromatin. Of the 6 genes identified, ERN1 (integral UPR gene that modulates a key plasma cell protein XBP1) and STX5 (SNARE protein facilitating ER to Golgi transport) emerged as high-priority candidates. This study reformulated the GLI2-IgM question from transcriptional regulation via CSR to secretory machinery regulation. The convergent framework produced testable hypotheses regarding whether GLI2 regulates IgM through the convergent targets.

Document Type

Master's Thesis

First Advisor

Sherine F Elsawa

Second Advisor

Megan Enos-Fournier

Third Advisor

Sarah Walker

Degree Name

Master of Science

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