Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Kai Fu

Abstract

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that can be distinguished based on histomorphological, phenotypic, and genetic features. B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U) is a subset of mature B cell lymphoma contains one or more features that overlap BL and DLBCL. Previous molecular analyses prove there is a biological continuum between BL and DLBCL based on the activity of MYC. Herein, in order to resolve the molecular heterogeneity of BCL-U, we tested whether a targeted expression profiling panel could categorize tumors as BL and DLBCL. Among these MYC driven lymphomas, those with concurrent MYC and BCL2 dysregulation are especially a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy and high risk of refractory. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support the rapid proliferation. Translation initiation inhibitor rocaglates were identified as the most potent drug across all MYC driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. Surprisingly, we found this class of compounds does not inhibit translation by depleting the abundance of eIF4A in eIF4F, but more likely acts as a selective roadblock to prevent ribosome scanning. Furthermore, proteome wide quantification demonstrated rocaglate induced selective repression of multiple critical oncoproteins beside MYC in B cell lymphoma including NEK2, MCL1, AURKA, PLK1 and several transcription factors that generally considered undruggable. Finally, (-)-SDS-1-021, the most promising rocaglate, was confirmed highly potent as single agent, and displayed significant synergy with BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in patient derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.

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