U01CA280984

Dysregulated Mechanoinmunology of Epigenetics-Driven Lymphomas - Project Summary

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) arise from germinal center (GC) B cells, which are at a stage where precursor B cells undergo rounds of proliferation, edit their immunoglobulins through somatic hypermutation and class-switch recombination, and undergo affinity selection through interactions with T follicular helper (TFH) cells and follicular dendritic cells (FDCs). The entry to and exit from the GC reaction require extensive changes in gene expression, which are controlled by transcription factors that recruit co-activators or co-repressors to drive epigenetic and transcriptional changes. The dysregulation of these molecular programs disrupts normal B cell differentiation and contributes to FL/DLBCLs.

Previous studies have indicated that EZH2 regulates the hyperproliferative nature of GC B cells and that gain-of-function mutations of the EZH2 Y641 residue "initiate" lymphomagenesis by attenuating the GC B cell requirement for TFH cell help and shifting the dependency to FDCs through increased expression of receptors through which B cells interact with these stromal cells. EZH2Y641F GC B cells evade TFH-directed clonal selection and affinity maturation, leading to lymphomagenesis. Interestingly, compared to EZH2WT, GC B cells carrying EZH2Y641F show increased and decreased BAFFR and CD40 expressions, respectively, and escape CD40L blockade-mediated impairment of the GC reaction. It is unclear whether the impairment of TFH help manifests as dysregulation of the mechanical control of TFH-B immunological synapse (IS) and alteration of their intercellular receptor-ligand interactions and signaling in FL/DLBCLs.

The overarching hypothesis is that, in contrast to GC B cells with EZH2WT, the EZH2Y641 mutation in GCB DLBCL/FL results in dysregulation of key immunoreceptors mediating the interactions of GC B cells with TFH cells and FDCs, leading to altered receptor forces, ligand binding, and mechanotransduction. This dysregulated receptor mechanobiology impacts downstream B cell signaling, epigenetics, and sensing of lymphoid microenvironmental cues responsible for extinguishing the "pseudo-malignant" phenotype of GC B cells, thereby driving the cancerous transformation of B cells. Our transcriptomic analysis suggests changes in the levels of proteins involved in B-FDC and B-TFH interactions, which should affect cellular function. The goal is to understand how the dynamic epigenetic states of DLBCL/FL-driving EZH2Y641 mutations dysregulate B cell mechanobiology, leading to malignancy.

Georgia Tech Research

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Georgia United States

State-Wide

Research Projects in Physical Sciences-Oncology (U01 Clinical Trial Optional) (PAR-22-147)

Amendment Since initial award the total obligations have increased 190% from $532,624 to $1,542,866.