Yen Lieu

Lead drug discovery projects on obesity and type II diabetes. Successfully explain the mechanism of action of the drug compound for the first project using my self-generated in vitro data. Identify and validate bat-inspired drug targets. Propose target validation plans with Go/No go decision points. Develop assays. Design, manage, and coordinate additional assays and in vivo animal studies with CROs. Serve as a subject matter expert to support project teams. Conceive a strategy to identify de novo metabolic targets while Paratus’ Bat Engine was being built and collaborate with a colleague to produce a list of targets by comparative genomics of bat traits. Train team members on lab techniques

A founding scientist who led multiple drug programs in metabolic liver diseases, drove the development of Arnatar's first drug program from target selection to IND-enabling studies, and creatively conceived and designed the lead siRNA molecule for the first program, which is set to enter a Phase I clinical trial in 2025. Contributed to the development of a siRNA design method, modified the method to make it more effective, used the revised method to design siRNAs for all of Arnatar’s siRNA drug programs, and devised strategies to optimize siRNA for activity and safety. Developed and executed high-throughput screening and in vitro assays and pharmacology studies. Managed and executed in vivo pharmacology and toxicology studies (dosed drugs, sampled blood, harvested organs) and developed mouse models of human liver diseases

Led a $5 million drug discovery project funded by Celgene/Bristol Myers Squibb (BMS) to develop novel drugs for the treatment of hematological and solid cancers with RNA splicing factor mutations in SF3B1, SRSF2, U2AF1: High-throughput screened 50,000-small molecule library for inhibitors of mutant SF3B1, SRSF2, and U2AF; performed validation studies to obtain 12 hit compounds, identified structure-activity relationships, executed optimization and MOA studies; performed CRISPRi screens; high-throughput screened for chemical compounds to rescue the erythroid differentiation defect in mutant SF3B1 Myelodysplastic Syndromes (MDS); collaborated with Columbia University high-throughput screening facility headed by Dr. Chuck Karen and with the medicinal chemistry group headed by Dr. Brent Stockwell; set up the Drug Discovery laboratory space with over $250K of equipment; supervised and mentored several technicians; presented work at all BMS-Columbia University Meetings. Conceived and designed the study and performed the experiments using SF3B1 CRISPR cells, normal human CD34 cells, and MDS patient cells to demonstrate that MAP3K7, encoded by a SF3B1 mutant-induced misspliced transcript, acts on the p38MAPK pathway to cause aberrant erythroid differentiation and apoptosis, leading to anemia as seen in MDS patients harboring SF3B1 mutations that account for a quarter of the MDS patients (first and co-corresponding author on paper deposited on BioRxiv and later published in PNAS 2022); the data from this work served as the foundation for our successful Celgene grant application. Generated CRIPSR/Cas9 knock-in tagging of SF3B1 mutant and WT K562 cells that were instrumental in helping to re-jumpstart a study that was published in Molecular Cell (co-second author). Wrote several grant awards: half of the Evans MDS grant; most of the $5 million Celgene/BMS grant based entirely on my data; some parts of a NIH R35 grant that was awarded to Dr. Manley

Studied the functional genomic consequences of the RNA splicing factor SF3B1, SRSF2 and U2AF1 mutations in the pathogenesis of Myelodysplastic Syndromes by the generation of knock-in mutational cell lines using CRISPR/Cas9 genome editing technology, analysis of RNA-sequencing data, and execution of functional studies; published SRSF2 mutant splicing mechanism as a co-first author on a PNAS 2015 paper. Investigated the contribution of DNA methyltransferase DNMT3a and methylcytosine hydroxylase TET2 to the DNA damage response by radiation using mouse models, leukemic cell lines and CRISPR-induced knockout of DNMT3a in human embryonic stem cells. Collaborated with Ross Levine’s laboratory at MSKCC, New York City on their DNMT3a projects, co-authors in Leukemia and Nature Medicine papers

Illuminated the significance of CD58 genomic inactivation in B-cell lymphoma in immune escape and in cancer cell signaling; investigated promoter methylation as another mechanism of surface CD58 loss. Proposed the model for immune escape from both T-cells and NK cells through loss of both Human Leukocyte Antigen and CD58 in DLBCL lymphoma; published as a co-first author in a Cancer Cell paper

Laboratory relocation

Successfully proposed and wrote all of the specific aims for a funded NIH RO1 grant (R01ActHL085279; “Role of C-myb in Hematopoiesis and Cancer”) for Dr. E.P. Reddy. Conceptualized and performed the study to demonstrate that conditional disruption of proto-oncogene c-myb in hematopoietic stem cells of mice leads to loss of self-renewal due to impaired proliferation and accelerated differentiation; published as a first and co-corresponding author in a PNAS 2009 paper. Designed and conducted the study to determine that the transcriptional factor c-myb is required for the function of adult myeloid progenitor cells in mice; listed as a first and co-corresponding author in a Cell Cycle article. Examined the role of c-myb in BCR-ABL-induced leukemogenesis and in myc mouse models of lymphomas. Collaborated in setting up a biochemical assay based on the refolding of denatured firefly luciferase to screen a compound library for inhibitors of heat shock protein 90 (co-author in Eur J Cancer). Wrote Institutional Review Board protocols

Thesis title “The role of the proto-oncogene c-myb in hematopoietic development and function.” Self-generated a conditional c-myb knockout mouse using embryonic stem cells and the Cre-Lox system to determine the roles of the transcription factor c-myb in T and B cell development and immune function by cross-breeding with tissue-specific Cre mice (first author in PNAS 2004). Served as a subject matter expert in generating the conditional B-myb knockout mouse model (co-author in a PNAS 2014). Examined the role of c-myb in normal mouse mammary development and cancer; demonstrated that A-myb is not required for spontaneous mammary tumor development induced by c-myc, ras, neu or wnt-1 transgenic mouse model

Helped in the development of a bioassay to track the in vivo response of alloreactive T cell populations to the major and minor histocompatibility antigens and in the determination of the requirement for CD28 co-stimulation in the recognition of allogeneic MHC antigens (co-author in several publications). Assisted in the demonstration that complement C3 contributes to autoimmune diabetes in the nonobese diabetic (NOD) mice and that B cell-mediated MHC class II antigen presentation is required for T cells activation in their attack on islet beta cells of NOD autoimmune diabetic mice (co-author in several publications)

Determined the effects of carnitine on coenzyme A profiles in freshly isolated rat liver cells after inhibition of acyl-CoA dehydrogenases with chemical compounds to model human fatty acid -oxidation MCAD and SCAD deficiencies; published as first author in an Am J Physiology article. Re-jumpstarted seminal study by revising PI’s model of hyperinsulinism-hyperammonemia syndrome; discovered novel mutation in the glutamate dehydrogenase gene and demonstrated that the hyperinsulinism-hyperammonemia syndrome in children is caused by those mutations in the glutamate dehydrogenase gene; published as a second author after the PI Dr. Stanley in a NEJM paper