The Biology of Mutant STAT6 in Follicular Lymphoma

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Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma (NHL) in the US, with over 100,000 patients living with the disease. While survival rates at 10 years have improved, almost all patients with FL receive multiple chemo- or immunotherapies over their lifetime and most eventually relapse and progress. There exists no highly effective targeted therapy for FL and the standard of care for FL patients remains largely based on chemoimmunotherapy. New drugs like the BTK inhibitor ibrutinib and the PIK3CD/PI3Kδ inhibitor idealisib have improved the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, these drugs are less effective in FL or are linked to serious side effects. Over the last eight years we have contributed to the discovery and initial functional characterization of recurrent mutations in FL, including in the SWI/SNF component ARID1A, linker histones (HIST1H1 B-E), IRF8, the mTOR regulator RRAGC, various components of the autophagy and mTOR regulator vATPase (ATP6V1B2, VMA21) and STAT6. One of the important genes that emerged from our efforts is Signal Transducer and Activator of Transcription (STAT6), which is mutated in 11-23% of all FL and transformed FL (tFL). Frequent mutations in STAT6 have also been described in primary mediastinal B cell lymphoma (PMBCL), Hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). STAT6 is part of the IL-4/JAK/STAT6 survival axis of B cells, which is also activated by elevated IL-4 levels present in FL LNs. The FL-associated mutations in STAT6 target amino acid hotspots, which are located in the STAT6 DNA binding domain. We have demonstrated that mutated STAT6 proteins result in the hyper activation of the expression of known STAT6 target genes (e.g. FCER2, CISH, CCL17, NFIL3). The identification of these gain-of-function properties changed the prevailing view of lymphoma-associated STAT6 mutations, which previously were believed to be hypomorphs. There remain however important unanswered questions pertaining to the molecular properties and functional consequences of mutated (MUT) STAT6 in lymphoma that are the focus of this proposal. These include the delineation of genome-wide binding sites of MUT as compared with WT STAT6 in B cells and the complete characterization of the genes that are transcriptionally regulated by MUT STAT6. Furthermore, the properties and biological consequences of the transcriptional programs that are activated or repressed by STAT6 in FL B cells or normal germinal center B cells are largely unknown. There is also untapped potential for the future targeting of the IL-4/JAK/STAT6 axis in FL and our proposed studies aim at providing the rationale to inform such studies. Finally, we will explore the interactions between STAT6 MUT FL B cells and the FL lymphnode resident microenvironment, especially with regards to T cell subsets.