Research Projects

The Zhang Lab seeks to understand how RNA dysregulation, altered antigen presentation, and immune interactions drive hematopoietic malignancies. Our research integrates functional genomics, single-cell and spatial multi-omics, stem cell biology, and cancer immunology to uncover mechanisms of malignant transformation and develop next-generation immunotherapies.

Our Vision

Our long-term goal is to bridge RNA biology, stemcell biology, and cancer immunology to understandhow malignant cells emerge, evade immunesurveillance, and resist therapy-and to translatethese discoveries into precision immunotherapiesfor patients with blood cancers.

R-Loops and Epigenetic Regulation in Hematopoietic Stem Cells

R-loops are three-stranded nucleic acid structures that play important roles in transcriptional regulation, genome stability, and cellular identity. However, their functions in hematopoietic stem cell maintenance, differentiation, and malignant transformation remain poorly understood. 

We are developing and applying innovative single-cell R-loop mapping technologies to investigate how R-loop dynamics regulate gene expression, epigenetic states, and hematopoietic stem cell fate. By integrating functional genetic screens and multi-omics approaches, we aim to identify R-loop-associated regulatory mechanisms that contribute to clonal hematopoiesis and leukemia development.

RNA Mis-Splicing, Antigen Presentation, and Immune Evasion in Myeloid Malignancies

Mutations in RNA splicing factors are common in myelodysplastic syndromes (MDS) and related hematologic malignancies, yet how these mutations influence immune recognition remains incompletely understood. 

Our research investigates how aberrant RNA splicing disrupts MHC class II antigen processing and presentation, enabling mutant hematopoietic cells to escape immune surveillance. We focus on the molecular consequences of splicing factor mutations, including dysregulation of the SPPL2A-CD74 pathway, and their effects on interactions between hematopoietic stem and progenitor cells and the immune microenvironment. 

Using genetically engineered models, functional genomics, and genotype-informed single-cell and spatial transcriptomics, we aim to define mechanisms of immune evasion and identify therapeutic strategies that restore antitumor immunity.

Engineering Next-Generation TCR-T Cell Immunotherapies for Blood Cancers

Despite major advances in cancer immunotherapy, effective T-cell therapies for myeloid malignancies remain limited by a shortage of suitable tumor-specific antigens and the immunosuppressive tumor microenvironment.

We are developing innovative T-cell receptor (TCR)-based immunotherapies targeting leukemia-associated antigens, including neoantigens generated by aberrant RNA splicing. Our approaches include engineered single-chain TCR (scTCR) platforms, optimized T-cell signaling, and strategies to overcome immunosuppressive pathways such as TGF-β signaling.

By combining antigen discovery, protein engineering, functional genomics, and preclinical disease models, we aim to develop more potent, specific, and durable cellular immunotherapies for hematologic malignancies.