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Linda Chan, PhD

Research Scientist, Internal Medicine (Hematology)

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Linda Chan, PhD

Research Summary

By studying clinical outcome data to identify predictors of clinical outcomes in high-risk B-cell leukemia (COG P9906), Dr. Chan identified BCL6 as a novel therapeutic target in high-risk MLL-rearranged B-cell leukemia. In addition, her work on metabolic reprogramming in B-cell leukemia has helped establish a new paradigm of how B-lymphoid transcription factors repress glucose and energy supply to set low thresholds for negative selection of transformed B-cells based on energy stress. More recently, She investigated functional interactions of oncogenic genetic lesions across multiple signaling pathways in B-cell leukemia. Reflecting her keen interest in preclinical translational research, she developed an innovative therapeutic strategy based on pharmacological reactivation of divergent pathways to prevent drug resistance in B-cell leukemia.

Extensive Research Description

1. Metabolic gatekeeper functions of B-lymphoid transcription factors. B-lymphoid transcription factors (e.g. IKZF1 and PAX5) mediate B-cell lineage commitment; however, genetic lesions in B-lymphoid transcription factors are found in more than 80% of B-cell leukemia cases. Combining gene expression analysis with a CRISPR-based genetic screen, Dr. Chan discovered that B-lymphoid transcription factors unexpectedly function as metabolic gatekeepers to safeguard against transformation. Thus, the highly frequent genetic defects in B-lymphoid transcription factors in B-cell leukemia cases represent a critical mechanism to subvert functions of the metabolic gatekeepers to fuel leukemic transformation. In collaboration with other members of the laboratory of Dr. Markus Müschen, she identified energy abundance as central determinant of negative B-cell selection and sets the threshold for removal of pre-malignant clones. Furthermore, she contributed to the discovery of PP2A – a tumor suppressor in many types of cancer – as a unique vulnerability and potential therapeutic target in B-cell malignancies.

2. Feedback control of oncogenic signaling in B-cell malignancies as therapeutic target. Malignant transformation typically involves cooperation of multiple genetic lesions. On this basis, one would predict that acquisition of additional oncogenic lesions would promote tumorigenesis. However, by studying genetic interactions of oncogenic drivers across multiple signaling pathways in combination with single-cell mutation and phosphoprotein analyses of B-cell leukemia cases, Dr. Chan identified convergence on one principal oncogenic driver as a critical step in leukemia initiation and progression. In addition, she developed an innovative therapeutic approach based on pharmacological reactivation of the divergent pathway to prevent drug resistance and relapse. In collaboration with other members of the laboratory of Dr. Markus Müschen, she investigated genetic and small molecule modulation of oncogenic signaling pathways including PI3K/AKT and ERK and contributed to the discovery of feedback control of oncogenic signaling as therapeutic target in B-cell malignancies.

3. BCL6 represents a therapeutic target in high-risk MLL-rearranged B-cell leukemia. Chromosomal translocations involving the mixed lineage leukemia (MLL) gene account for ~10% of B-cell leukemia cases and are associated with dismal clinical outcomes with overall survival rates of <50%. Dr. Chan discovered MLL-dependent transactivation of BCL6 as a previously unrecognized requirement for MLL fusion-driven leukemic transformation. She devised a new therapeutic strategy for this disease based on combinatorial treatment with BCL6 inhibitor and BH3-mimetic ABT-199 (a BCL2-specific inhibitor).


Coauthors

Selected Publications