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Using molecular, biochemical, cellular and in vivo methods, the Felix lab studies the pathobiology of KMT2A-rearranged (KMT2A-R) leukemias to find better ways to treat and prevent them.
In the early 1990s, Dr. Felix invented panhandle PCR cloning strategies to discover the genomic features of the translocations and disrupted partner genes. The genomic breakpoint junctions in a pair of monozygous infant twins with leukemia established an in utero origin of the translocation. The breakpoint junctions proved useful biomarkers to trace the onset of KMT2A translocations to exposure to TOP2 poison chemotherapy in the treatment-related cases. Parallel studies showed the translocation breakpoints are TOP2 cleavage sites in vitro, substantiating a mechanistic role of disturbed TOP2 cleavage as the DNA damage mediator. They discovered variations in particular TOP2 poison detoxifying enzymes (NQO1, CYP3A4) as host risk factors for these translocations.
Dr. Felix co-invented a new high-throughput sequencing technology for detecting and mapping TOP2 cleavage genome-wide. The cell line studies using this method uncovered enriched TOP2 cleavage in all genes involved in oncogenic translocations. Dr. Felix and her colleagues also unraveled associations between TOP2A cleavage and histone marks of gene activation including transcription and enhancers, which have provided leads to possible new treatments.
In addition, despite intensive chemotherapy the KMT2A-R leukemias notoriously are cell-death resistant. Therefore, Dr. Felix and her team also are investigating molecularly targeted agents to surmount cell death resistance, and showed that one such agent, ribavirin, a repurposed antiviral drug that targets EIF4E, can post-transcriptionally downregulate anti-apoptotic proteins in KMT2A-R leukemia that cause cell death resistance.
Dr. Felix’s interests in KMT2A-R leukemia extend to building models in zebrafish embryo as a developmental tool to recapitulate leukemogenesis in infants. Her KMT2A-R leukemia research program encompasses TOP2 DNA damage mechanisms, molecular epidemiology, disease biomarkers, and developmental origins of the translocations and novel treatments.
Leader, Normal and Malignant Hematopoiesis Research Affinity Group
Dr. Felix uses molecular, biochemical, cellular and in vivo methods to investigate the pathobiology of leukemias with KMT2A (MLL) translocations. Leukemias with these translocations affect infants and young children or occur as a complication of type II topoisomerase (TOP2) poison chemotherapies used for anti-cancer treatment. She aims to develop better treatment and prevention approaches for these leukemias, which have a poor prognosis.