Linde A. Miles, PhD
Postdoctoral Research Associate
Memorial Sloan Kettering Cancer Center
am currently a postdoctoral research associate with Dr. Ross L. Levine in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center (MSKCC). My research across my graduate and postdoctoral training has centered on investigating the underlying biology of tumorigenesis and innovative therapeutic strategies to combat disease. I performed my graduate training at Johns Hopkins University under the mentorship of Dr. Charles M. Rudin and received my PhD in 2016. The essence of my graduate work was the identification of crucial host proteins for Seneca Valley Virus (SVV), one of the earliest oncolytic viruses with therapeutic potential in small cell lung cancer (SCLC). As part of this work, I performed the first genome-wide CRISPR screens at MSKCC and identified and characterized the cellular receptor for SVV. These studies, supported by two one-year Lung Cancer Research Foundation grants and published as a first-author manuscript in JCI (2017), have provided a necessary biomarker for patient stratification in future clinical trials. In my postdoctoral studies in the Levine Lab, I have investigated the clonal architecture of myeloid malignancies in clinical isolates utilizing state-of-the-art single cell multi-omic approaches. This work, recently published as a co-first author study in Nature (2020), elucidated synergistic mutational combinations in clonal dominance and uncovered clone-specific immunophenotypes during leukemogenesis. The insights gained from these studies have allowed me to develop a new suite of combinatorial mouse models that more accurately recapitulate the stepwise mutational acquisition during clonal evolution. Initial studies with these models have revealed clone specific differences in disease phenotype, latency, and resultant immunophenotype that confirm our findings in clinical isolates. This work has been supported by a Leukemia and Lymphoma Society Career Development Fellow award, a MSKCC Marie Josée Kravis Women in Science Endeavor (WiSE) Fellow award, and currently through the NCI as a K99/R00 award. My independent research program leverages the combined power of cutting-edge single cell multi-omics in clinical isolates and the innovative preclinical models mentioned above to dissect the evolutionary steps that occur during malignant transformation. As such, I am able to delineate the cellular alterations in gene expression, protein signaling, and hematopoietic output as an antecedent clone acquires a new mutation and with certain mutations, determine the plasticity of these alterations through the use of reversible mutant alleles. Studies from my research program have the potential to elucidate the evolutionary trajectories in leukemogenesis, redefine important leukemic immunophenotypes, and connect mutant-specific cellular changes to clonal fitness and transformation. Moreover, I aim to discover novel clone-specific vulnerabilities with therapeutic potential through genetic and chemical screens. In the short term, studies from my lab will focus on already generated models centered on the common AML mutation, NPM1c, to delineate the importance of precise mutation order in transformation, how combinations of additional mutations with NPM1c affect clonal trajectories, and the characterization of downstream cellular alterations in NPM1c-mutant clones. In the long term, I will expand to investigate additional mutational combinations and assess new single-cell multi-omic platforms to broaden our understanding of cellular changes during clonal evolution.