Diffuse large B-cell lymphomas (DLBCL) arise from B-cells transiting different stages of the germinal center (GC) reaction. We have an incomplete picture of the regulatory logic and circuits that become disrupted in subtypes of DLBCL. This is especially true in Activated B-cell-like (ABC) subtype, an aggressive subset of tumors that respond poorly to standard-of-care chemotherapy and have a dismal prognosis. To uncover novel regulatory circuits we leverage chromatin accessibility maps (regulomes) produced by ATACseq and develop a computational framework to quantify gain or loss of accessibility across regulatory elements of expressed TFs. Here, we hypothesize that ABC-DLBCLs depend on the activity of BATF to drive their oncogenic transcriptional programs. We seek to uncover mechanisms of gene regulation by BATF including decipher the mechanisms by which BATF and co-factors assemble on chromatin cooperatively, the mechanisms that mediate a highly clustered chromatin accessibility imprint at critical ABC loci.
Aim 1 : To identify and validate the direct targets of BATF in B cell lymphoma. We will perform ATACseq and RNAseq in DLBCL cell lines and an additional cohort of DLBCL tumors and normal B-cells, and map regulatory elements including putative BATF targets and LCRs.
Aim2. To determine the mechanisms though which BATF regulates gene expression in ABC-DLBCL. We hypothesize that BATF is essential in ABC-DLBCL and regulates gene expression by enabling chromatin accessibility, binding of additional factors, and accessibility and looping of LCRs.
Aim3. To define the contribution of BATF to the ABC phenotype in vitro and in vivo. We will examine the role of BATF on the growth, survival, and differentiation of ABC cells after BATF depletion. We hypothesize that in the absence of BATF, ABC cell lines cannot maintain their identity and will die or differentiate.
The proposed research will significantly advance our understanding of how BATF contributes to the survival of aggressive B cell lymphomas. The use of chromatin accessibility maps directly in tumors will reveal transcriptional and epigenetic vulnerabilities and provide important information for rational therapeutic design.
