Dr. Linde Miles: 2021 CDP Achievement Award Winner

Dr. Miles

2021 LLS-CDP FELLOW ACHIEVEMENT AWARD

Dr. Linde Miles received her Ph.D. in Pharmacology & Molecular Sciences from Johns Hopkins School of Medicine in Baltimore, MD in 2016. In the lab of Dr. Charles Rudin, her graduate work focused on the identification of essential host proteins for the Seneca Valley Virus, an oncolytic virus with preclinical import in small cell lung cancer. Dr. Miles received the LLS CDP Fellow award while doing a postdoctoral fellowship at the Memorial Sloan Kettering Cancer Center in the lab of Dr. Ross Levine. Her research aimed to dissect clonal evolution during leukemic transformation and understand how mutation order impacts disease development. Harnessing her expertise in mechanistic-based studies and innovative single cell assays, and mouse modeling, her research investigated how mutations affect clonal evolutionary trajectories during leukemic transformation, a fundamental question in the field. Dr. Miles is extremely passionate about transforming our understanding of leukemic biology and committed to continuing this focus in her independent research career. She is currently Assistant Professor at the Cincinnati Children's Hospital Medical Center. Her independent lab continues to build upon her postdoctoral work interrogating the stepwise process of disease development and the cellular alterations that drive leukemogenesis..

"I am forever thankful to the LLS for supporting me and my work with the Career Development Program (CDP) Fellow Award and more recently, with this CDP Achievement Award. I received the original CDP Fellow Award when I was still quite new to the leukemia field in the lab of Dr. Ross Levine. The award, in combination with Dr. Levine’s mentorship, was instrumental in catapulting my career in the field and helping grow my network of peers, mentors, and colleagues. This outstanding fellowship program also provided additional confidence in my science, the importance of our questions in the field, and my potential as a leader in the field. When I look back on my postdoc, the CDP award was one of the first, important stepping stones on the path to securing my goal of having an independent research lab. Fellowship programs, like this one, are fundamental for young researchers’ careers – it certainly was for mine.

I am also thankful to have received the Achievement Award as I begin my own lab at Cincinnati Children’s. The caliber of research and careers of the previous winners are just phenomenal. I am extremely honored to be named among them and thank the LLS for their continued commitment to the promotion of postdocs and junior faculty in the leukemia field."

    Dr. Miles was awarded the CDP Fellow Award in 2018 for her project titled Interrogating the functional contributions of RAS mutations in AML:

    Acute myeloid leukemia (AML) affects approximately 20,000 new US patients every year, with more than one third succumbing to the disease within five years. Studies of many AML patients suggest that over 20% have mutations in genes that encode proteins involved in the RAS-MAPK growth signaling pathway. Mutations in this pathway occur in almost every type of human cancer. Unfortunately, there are no effective therapies that directly target RAS or MAPK. Given their widespread importance in many cancers, a better understanding of these proteins in AML is needed.

    Though RAS has received a great deal of attention since its discovery decades ago, much of that attention has been on the very important work of identifying mutations and how they affect RAS function. However, the role of RAS as a cooperating oncogene working together (or in opposition) with other proteins has received much less attention. In AML, RAS mutations commonly co-occur with mutations in NPM1, a protein that is involved in genome stability and cellular growth. RAS mutations also co-occur with a class of proteins called epigenetic modifiers that orchestrate gene expression through chemical modifications of proteins and DNA. Analysis of DNA from patients suggests that a stepwise accrual of mutations drives AML development; some mutations, such as those in epigenetic modifiers (DNMT3a and TET2), occur early in the formation of AML, while other mutations occur later. This suggests that the order of acquisition of mutations is likely important for the formation of AML. However, for RAS and NPM1, it can be difficult to discern in which order the mutations occur and if this order leads to differences in the resulting disease. I will use experimental mouse models to characterize the paths resulting from differences in mutational order with the goal of identifying critical differences and therapeutic liabilities in disease progression. We will express RAS and NPM1 in varying temporal orders alone or in the background of established DNMT3a and TET2 mutations. These mouse studies will simulate the initiation, development, and maintenance of RAS mutant AML observed in patients and allow a better understanding of the role RAS proteins play in this disease. By answering these fundamental biological questions, we hope to identify novel targets that can be exploited for effective therapies for AML patients with RAS pathway mutations and anticipate the potential of co-occurring mutations to prevent the emergence of high-risk disease in RAS mutant AML patients..

    Funding from the LLS during the award period (2018-2020) allowed her to advance research across multiple research topics. Some highlights:

    • NPM1 and NRAS mutations in AML: Initial studies during the grant funding period investigated the relationship between the NPM1 and NRAS mutations and impact of mutation order in AML formation. Future studies will delineate the different mechanisms of cooperation between mutant Npm1 and different Nras mutations in Ras-mutant disease.
    • The clonal architecture of RAS-mutant AML: utilizing single cell DNA sequencing and simultaneous scDNA seq and cell surface protein expression analysis, she has found that RAS-mutant clones: 1. were more frequently subclonal but often occurred more than once in distinct subclones 2. represented “late” mutations by evolutionary trajectory analysis, 3. could synergize with NPM1 mutations to drive clonal dominance/expansion but to a less degree than a similar co-mutant pair, NPM1/FLT3, and 4. were enriched for high CD11b expression compare to RAS WT clones. She has since expanded the original antibody panel for single cell analysis to now include 45 antibodies, which provide better resolution to both stem/progenitor populations as well as mature lineages. Future studies will continue to investigate these clonotype-immunophenotype relationships in RAS-mutant AML and elucidate the downstream effects of these alterations in our mouse models of Ras-mutant myeloid transformation.

     

    All first author publications and presentations during the award period:

    • Miles et al. Nature (2020)
    • Miles et al. ASH Annual Meeting (2019)