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The Choi lab primarily employs functional proteogenomic approaches to map the molecular landscape of lymphoid malignancies and identify novel therapeutic targets. These unbiased studies reveal that lymphoid cancers exploit oncogenic signaling proteins essential for normal lymphoid cell development and function. Targeting these lymphoid-specific pathways offers promising opportunities for lymphoma therapy.
What We Focus
1. Our lab is uncovering how ubiquitin signaling safeguards B cells from malignant transformation.
We have identified tumor-suppressive E3 ligases—Fbxl8 and KLHL6—that act at key regulatory nodes controlling cell cycle and mRNA stability. These ligases serve as molecular gatekeepers, and their loss enables lymphoma cells to evade stress responses and sustain oncogenic programs. Moving forward, we aim to map the ubiquitin-mediated control network in B-cell malignancies and harness its vulnerabilities for therapeutic innovation. By decoding how the cell’s degradation machinery defends against cancer, we hope to turn the logic of tumor evolution into a blueprint for precision treatment.
2. Our lab investigates how malignant B cells exploit BCR signaling to sustain survival and how this pathway can be disrupted to treat aggressive lymphomas.
We have uncovered tumor suppressors, such as KLHL14 and LAPTM5, that naturally restrain BCR activity—KLHL14 by reducing immature BCR subunits in the ER, and LAPTM5 by promoting BCR degradation through the lysosomal pathway. When these regulators are lost, lymphoma cells amplify oncogenic BCR-NF-κB signaling and become resistant to targeted therapies. By uncovering new molecular brakes on this pathway, we aim to develop strategies that restore control over BCR signaling and overcome drug resistance in B-cell malignancies.
3. Our lab is charting the molecular logic of lymphoma vulnerabilities through high-resolution CRISPR screening and signaling network analysis.
By integrating functional genomics with pharmacologic perturbation, we aim to define how oncogenic circuits—such as BCR and PI3K-NF-κB pathways—are dismantled by therapeutics like glucocorticoids. We use genome-wide CRISPR-Cas9 screens in engineered multi-omics-enabled cell models to uncover subtype-specific dependencies and resistance mechanisms. Our ultimate goal is to transform these mechanistic insights into rational combination therapies that selectively collapse tumor survival networks while sparing normal cells.
How We Do
Utilizing CRISPR Screens to Unravel Lymphoma Biology
A. General Scheme for CRISPR-Cas9 genetic screens:
We have applied unbiased, genome-wide loss-of-function CRISPR-Cas9 genetic screens to elucidate tumor subtype-specific drivers of oncogenesis. Furthermore, by employing these approaches in combination with drugs in aggressive B-cell lymphomas, we have identified synthetic lethality targets and the molecular mechanisms of action of glucocorticoids, as well as analyzed how these targets regulate oncogenic signaling networks. (Choi et al., Cancer Cell (2024))
B. Epistasis Screens:
We have applied these methods to investigate epistatic interactions of a specific gene by adapting the whole-genome CRISPR screening techniques. Using this approach, we have explored the functional mechanisms of tumor suppressor-like genes such as KLHL14. (Choi et al., PNAS (2020))
C. Fluorescence-Activated Cell Sorting (FACS)-Sorted CRISPR Screens:
We have applied these methods to uncover regulators of intracellular signaling cascades, surface antigen expression, and protein modulation, incorporating protocol adjustments tailored to each specific phenotype. (Bolomsky and Choi et al., Methods Mol Biol (2024))
Overall Approach
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