Histone 1 Mutations Drive Lymphomagenesis By Inducing Primitive Stem Cell Functions and Epigenetic Instructions through Profound 3D Re-Organization of the B-Cell Genome

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.23-23
• Main Authors: Yusufova, Nevin, Teater, Matthew R, Soshnev, Alexey, Kloetgen, Andreas, Osunsade, Adewola, Conway, Joseph, Doane, Ashley, Skoultchi, Arthur, Tsirigos, Aristotelis, David, Yael, Allis, C. David, Cesarman, Ethel, Melnick, Ari
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-127774

Somatic missense mutations in histone 1 genes occur in ~30% of follicular lymphomas and DLBCL and 85% of Hodgkin's lymphomas, with significant mutual co-occurrence among these alleles, most frequently involving H1C and H1E. We crossed constitutive H1C+/-H1E+/- mice with VavP-Bcl2 transgenic mice and observed significant acceleration of lymphomagenesis (p=0.0001). Lymphoma H1 mutations affect the H1 globular domain or C-terminus. We found that the globular domain mutants fail to insert into chromatin whereas C-ter mutants fail to compact chromatin as shown by atomic force microscopy, in vitro assembled nucleosome arrays, and FRET assays in live cells. Hence both types of mutation confer loss of function. Constitutive H1C/E knockout mice are healthy and have no overt phenotype. However, immunization with T-cell dependent antigen caused significant GC hyperplasia (p=0.013) and disruption of polarity due to expansion in the number of centrocytes. Notably, H1C/EDKO GC B-cells readily outcompeted WT GC B-cells in mixed chimera experiments indicating that they have superior fitness (p=0.0086). To understand the mechanism through which this occurs we performed RNA-seq in H1C/EDKO GC B-cells which revealed an aberrant gene expression signature composed almost entirely of transcriptional activation (n=721 upregulated and n=61 downregulated q=0.05, LFC=log(1.5)). Strikingly, these same genes are upregulated during induced pluripotency (iPS cell) reprogramming, and are normally silenced during early development by the PRC2 complex (p