A decade of genomic studies has revealed the landscape of mutations appearing in the genomes of Acute Myeloid Leukemias (AML). A subset of these mutations have been identified as AML-initiating events that create growth advantages in a hematopoietic stem/progenitor cell (HSPC). This leads to the early stages of disease, but the mechanisms by which these mutations act is poorly understood. This research program will study key AML-initiating events in both primary tumors and mouse models by generating comprehensive whole-genome transcriptomic and epigenomic data (RNA-seq, bisulfite-seq, ATAC-seq, single-cell RNA-seq, et al). My role will be to translate these large, complex data sets into conclusions and testable hypotheses about the precise molecular mechanisms by which these specific genetic mutations initiate AML. Doing so will require the development of new algorithms and statistical models, both areas of bioinformatics in which I am proficient. We will then leverage this knowledge to develop novel therapies. A second key question focuses on the 50% of AML patients who initially experience complete remission after chemotherapy, but ultimately relapse. Our previous work has shown that genome sequencing can often identify persistent leukemia-associated mutations in post-chemotherapy biopsies from these patients, even when they are in morphological remission. This lack of mutation clearance was strongly associated with risk of relapse, but was not absolutely predictive: a few patients with persistent mutations experienced long remissions, and others who cleared all mutations quickly relapsed. Two remaining questions with important clinical implications are: 1) Can sequencing of biopsies from additional post-treatment timepoints better define the trajectory of mutation clearance and offer additional prognostically useful information? 2) Could ultra-deep sequencing have detected the residual disease responsible for relapse, thus prompting earlier interventions? Having co-led the original mutation clearance study, and authored tools for tracking a tumor's clonal evolution through therapy, I have the required expertise to deign these studies, and analyze, visualize, and interpret these data. We are beginning clinical trials that use clearance to assign patients to more or less aggressive treatments and providing more clarity on the above questions will be a key part of translating these findings into robust clinical tests. My interdisciplinary skillset couples a deep understanding of the biology of AML with statistical acumen and expertise in designing new algorithms. My training, experience, and record of successful scientific contributions make me uniquely suited to drive the informatics and analysis aspects of these projects forward.
This project focuses on understanding how patients develop Acute Myeloid Leukemia, how to predict whether they'll relapse after treatment, and developing new therapies to treat them. Each of these goals requires taking ?big data? from experiments and applying computer programs and statistics that help to draw conclusions and generate new hypotheses about this deadly disease. Dr. Miller is an expert in doing so and has key experience in the genomics of AML, and this award will support his contributions to the project.
|Wong, Terrence N; Miller, Christopher A; Jotte, Matthew R M et al. (2018) Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun 9:455|
|Christopher, Matthew J; Petti, Allegra A; Rettig, Michael P et al. (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N Engl J Med 379:2330-2341|
|Miller, Christopher A; Tricarico, Christopher; Skidmore, Zachary L et al. (2018) A case of acute myeloid leukemia with promyelocytic features characterized by expression of a novel RARG-CPSF6 fusion. Blood Adv 2:1295-1299|
|Jacoby, Meagan A; Duncavage, Eric J; Chang, Gue Su et al. (2018) Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight 3:|
|Bansal, Dhruv; Vij, Kiran; Chang, Gue Su et al. (2018) Lenalidomide results in a durable complete remission in acute myeloid leukemia accompanied by persistence of somatic mutations and a T-cell infiltrate in the bone marrow. Haematologica 103:e270-e273|