Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

Yusufova, N., Kloetgen, A., Teater, M., Osunsade, A., Camarillo, J. M., Chin, C. R., Doane, A. S., Venters, B. J., Portillo-Ledesma, S., Conway, J., Phillip, J. M., Elemento, O., Scott, D. W., Béguelin, W., Licht, J. D., Kelleher, N. L., Staudt, L. M., Skoultchi, A. I., Keogh, M. C., Apostolou, E., … Melnick, A. M. (2021). Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture. Nature, 589(7841), 299–305. https://doi.org/10.1038/s41586-020-3017-y

Based on gene expression profiles, diffuse large B cell lymphoma (DLBCL) is sub-divided into germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. Two of the most common genomic aberrations in ABC-DLBCL are mutations in MYD88, as well as BCL2 copy number gains. Here, we employ immune phenotyping, RNA-Seq and whole exome sequencing to characterize a Myd88 and Bcl2-driven mouse model of ABC-DLBCL. We show that this model resembles features of human ABC-DLBCL. We further demonstrate an actionable dependence of our murine ABC-DLBCL model on BCL2. This BCL2 dependence was also detectable in human ABC-DLBCL cell lines. Moreover, human ABC-DLBCLs displayed increased PD-L1 expression, compared to GCB-DLBCL. In vivo experiments in our ABC-DLBCL model showed that combined venetoclax and RMP1-14 significantly increased the overall survival of lymphoma bearing animals, indicating that this combination may be a viable option for selected human ABC-DLBCL cases harboring MYD88 and BCL2 aberrations.

Journal: Nature PMID: 33299181 DOI: 10.1038/s41586-020-3017-y