Molecular Heterogeneity of BCL2/MYC Double Expressor Lymphoma Underlies Sensitivity to Histone Deacetylase Inhibitor

Introduction: Double expressor lymphoma (DEL) concurrently overexpressing BCL2 and MYC protein represent a high-risk phenotypic entity of diffuse large B-cell lymphoma. Evidence suggested that DEL may be molecularly heterogeneous. The aim of this study was to identify molecular subtypes of DEL with distinct biological features and potential therapeutic implications. Methods: Unsupervised transcriptome-based clustering was performed on tumor samples from 157 patients with DEL. Genomic, transcriptomic, and tumor microenvironmental alterations were integrated, as compared to 160 patients double negative for BCL2 and MYC protein. Preclinical models including cell lines and patient-derived xenograft models were established to investigate the effect of histone deacetylase inhibitor tucidinostat combined with doxorubicin on each DEL subtype. Results: We identified three molecular subtypes of DEL, namely, cluster 1 (C1, n = 48), cluster 2 (C2, n = 63), and cluster 3 (C3, n = 46), which shared recurrent high-frequency mutations of PIM1 and MYD88, and upregulation of NF-kappa B signaling pathway. Moreover, C1 was characterized by KMT2D mutations, upregulation of T-cell receptor signaling pathway, and increased infiltration of exhausted CD8+ T cells and M2 macrophages within the tumor microenvironment. Both C2 and C3 were characterized by CD79B mutations and upregulation of B-cell receptor (BCR) signaling pathway, but differed in oncogenic transcriptional factors, with REL family in C2 and POU family in C3. Tucidinostat combined with doxorubicin targeted the immune cell dysfunction in C1, and the closure of chromatin and downregulation of target genes involved in BCR signaling pathway in C2 and C3. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Genomics, Epigenomics, and Other -Omics, Tumor Biology and Heterogeneity No conflicts of interests pertinent to the abstract.