Table 1_MIZ-1 controls transcriptional programs required for BCR signaling, actin dynamics, and naïve B cell survival.xlsx

B cell receptor (BCR) signaling is required for the regulation of normal B lymphocyte development. However, many B cell lymphoma subtypes employ constitutive BCR signaling for transformation, survival, and growth. Here we report that mice expressing a POZ domain-deficient MIZ-1 (MIZ-1ΔPOZ), a well-known binding partner of the oncogene MYC, exhibit reduced surface receptor expression on naïve B cells and impaired BCR signaling. Transcriptomic and ChIP-seq analyses revealed that, in addition to autophagy related genes, MIZ-1 directly regulates genes involved in BCR signal transduction and actin cytoskeleton dynamics. Upon stimulation, MIZ-1ΔPOZ B cells show defective receptor clustering and impaired BCR-induced signal transduction via key signaling molecules such as SYK, RAF1, AKT and ERK. We demonstrate that these perturbations are associated with altered calcium flux and mitochondrial respiration. These defects upon BCR crosslinking specifically lead to decreased survival of follicular but not marginal zone B cells and impaired the expansion of MYC-dependent B cell lymphoma. Altogether, our data suggest that MIZ-1 is as a central integrator of BCR signaling which is essential for maintaining B cell function and keeping a balance between cell death and survival.