PARP14 is a novel target in STAT6 mutant follicular lymphoma.

The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.

PCMD-1 Organizes Centrosome Matrix Assembly in C. elegans.

Centrosomes, the major microtubule-organizing centers of animal cells, are essential for the assembly of a bipolar spindle during mitosis. Spindle defective-5 (SPD-5), the main scaffold protein of the centrosome matrix in Caenorhabditis elegans, forms a thin core around non-mitotic centrioles. Upon mitotic entry, the SPD-5-containing centrosome matrix expands in a Polo-like-kinase 1 (PLK-1)-dependent manner and this enables an enhanced microtubule nucleation activity during mitosis. How the non-mitotic centrosome core is formed and how this core facilitates robust SPD-5 expansion at mitotic entry remains unknown. Here, we present evidence that the coiled-coil protein pericentriolar matrix deficient-1 (PCMD-1) is necessary for the efficient loading of SPD-5, SPD-2, and PLK-1 to the non-mitotic centrosome core. Furthermore, we demonstrate that the absence of PCMD-1 disrupts pericentriolar material (PCM) recruitment and integrity. The expansion of centrosomes into spherical structures at the mitotic entry is compromised. We propose that PCMD-1 acts as a molecular platform for mitotic regulators and for components of the PCM, thereby allowing functional interactions between them, which in turn is necessary for the organization of the mitotic centrosome and, hence, spindle bipolarity.