Date of Award

Spring 2023

Project Type

Dissertation

Program or Major

Genetics

Degree Name

Doctor of Philosophy

First Advisor

Sherine Elsawa

Second Advisor

Xuanmao Chen

Third Advisor

Victoria Jeffers

Abstract

Waldenström macroglobulinemia (WM) is an indolent lymphoproliferative disorder with aberrant monoclonal immunoglobulin M (IgM) production that is associated with disease symptoms. Despite significant advances in our understanding of disease biology, the cell of origin remains largely unknown. Although WM therapy options have improved over the last decade, WM is still an incurable disease. Many studies have identified epigenetic dysregulation as a regulatory factor in WM malignancy. Here, we investigated the role of Mixed-lineage leukemia 1 (MLL1) histone methyltransferase in WM. We showed that MLL1 and its partner Menin are upregulated in WM patients. We also found that MLL1 knockdown and pharmacological inhibition of MLL1 complex using the menin-MLL1 inhibitor (MI-2) significantly reduced IgM levels in-vitro and in-vivo. Further we showed that MLL1 binds to multiple sites in the 5' Eμ enhancer of the IgM heavy chain (IGMH). We also found that MLL1 binding to IGH region was associated with increased histone 3 lysine 4 trimethylation (H3K4me3) enrichment at multiple MLL1 binding sites. Moreover, we described B cell receptor (BCR) repertoires of the currently available cell lines for WM (BCWM.1, MWCL-1 and RPCI-WM1). We also found abnormal transcription of immunoglobulin heavy chain (H-chain) and light chain (L-chain) transcripts with increased L:H-chain ratio in WM cell lines compared to normal B cells and this correlated with the amount of secreted IgM by each WM cell line. Finally, we identified that MI-2 inhibitor significantly reduced light chain expression in WM cells suggesting a role for MLL1 in regulation of light chain. Taken together, these results identify MLL1 as a regulator of IgM light and heavy chains that suggest MLL1 as a new therapeutic target for WM.

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