It is well established that E2A proteins activate the expression of tumor suppressors, EBF1, PAX5 and FOXO1, to promote the B cell fate. E2A and EBF1 are frequently mutated either by chromosomal translocations, point mutations or gene deletions in B-cell precursor acute lymphoblastic leukemia. However, it remains an enigma why EBF1 is not transcribed in multipotent progenitors, in which E2A is expressed at high levels. It has been shown that, by HiC and 3D-fluorescence in situ hybridization (3D-FISH), in multipotent progenitors the EBF1 locus was located at the nuclear lamina, in pro-B cells the EBF1 locus was located away from the lamina. In this study, using gain-of-function approaches, we show that enforced Zbtb7b expression inhibited B cell differentiation and caused rapid loss of EBF1 and Pax5 mRNA. Notably, Using 3D-FISH, we found enforced expression of Zbtb7b sequestered EBF1 locus to the nuclear lamina, and using live cell imaging, we show that, Zbtb7b primarily localized at nuclear lamina. We are now investigating whether and how the nuclear envelope and its interaction with the genome change during early B cell commitment using Damseq; and anti-Zbtb7b ChIP-seq provide fine mapping of potential interaction regions with nuclear lamina. These data indicate a novel role of Zbtb7b in B cell lineage commitment and potentially link EBF1 and Zbtb7b into a common pathway. Experiments are ongoing to further examine how sequestration of genes to the nuclear lamina relates to the development of lymphoid cells.

Citation Format: Yina Zhu, Cornelis Murre. Zbtb7b is involved in the association of EBF1 enhancer to the nuclear lamina during early B cell commitment. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A182.