Shu Lin
Program: Cancer Biology
Current advisor: Stephen Oh, MD, PhD
Undergraduate university: Vanderbilt University
Research summary
Myeloproliferative neoplasms (MPNs) are clonal hematologic disorders initiated in hematopoietic stem and progenitor cells (HSPCs) by coding mutations in the JAK-STAT pathway, which respond initially to JAK2 inhibitors such as ruxolitinib. However, up to 20% of patients progress to secondary acute myeloid leukemia (sAML), an aggressive malignancy with a median survival under six months and refractory to standard therapies. Epigenetic reprogramming is increasingly recognized as a central driver of this transformation. High-risk mutations in chromatin regulators (ASXL1, EZH2, SRSF2) are strongly associated with sAML progression. Further, ~94% of the heritable MPN risk variants are non-coding, yet their functional significance at the regulatory elements is largely unknown18. A critical gap in our understanding of leukemic progression is the absence of a genome-wide, single-cell map integrating chromatin accessibility, histone modification, and transcriptomes across MPN-to-sAML transition, leaving the cell. The proposed project will make three key contributions. Basic Science: First, it will challenge the prevailing paradigm by delineating the landscape of epigenetic reprogramming, rather than coding mutations in the JAK-STAT pathways alone, as a central driver of leukemic transformation. Second, it will address a major barrier to progress by generating the first integrated single-cell epigenomic resource for sAML with cutting-edge technology, enabling systematic interrogation of enhancer-gene dysregulation across disease states. In contrast to genes targeting alone, enhancer targeting may be more developmentally restricted and cell-type-specific, offering the potential for therapeutic intervention with less off-target effects as exemplified by BCL11A enhancer targeting in sickle cell anemia. Third, the combined computational and experimental framework will provide a generalizable strategy for identifying and functionally validating the regulatory genome, broadly applicable to other cancers and complex diseases. Collectively, these advances will nominate novel therapeutic targets for a disease with limited treatment options. Training Opportunity: As an MSTP trainee, this project will provide rigorous interdisciplinary training in computational (epi)genomics, functional (epi)genomics, and translational hematology, preparing me for a career as a highly successful independent physician–scientist.
Graduate publications
He F, Laranjeira AB, Kong T, Lin S, Ashworth KJ, Liu A, Lasky NM, Fisher DA, Cox MJ, Fulbright MC, Antunes-Heck L, Yu L, Brakhane M, Gao B, Sykes SM, D’Alessandro A, Di Paola J, Oh ST. 2024 Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms. J Clin Invest, 343(3):e172256.