Effects of C-terminal truncations of the histone acetyltransferase p300 on the growth and gene expression patterns of human diffuse large B-cell lymphoma cell lines

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s B- cell lymphoma, accounting for about 30% of these lymphomas in the United States. Large-scale genome analyses of DLBCL have identified mutations in the related histone acetyltransferases (HATs) p300 and CBP in approximately 15% of patient samples and patient-derived cell lines. The research presented herein characterizes two human DLBCL cell lines, RC-K8 and SUDHL2, which express C-terminally truncated HAT domain-deficient p300 proteins, p300ΔC-1087 and p300 p300ΔC-820, respectively. It is shown that p300ΔC-820 localizes to sites of active transcription in the nucleus, interacts with NF-κB transcription factor REL, weakly enhances REL-dependent transactivation, and has a half-life similar to wild-type p300. Results demonstrate that knockdown of p300ΔC-820 in SUDHL2 cells reduces cell proliferation in vitro. In RC-K8 cells, p300ΔC-1087 suppresses expression of the NF-κB target genes A20 and IκBα, both of which are cytotoxic when overexpressed in RC-K8 cells. Microarray analysis of p300ΔC1087 knockdown compared to wild-type RC-K8 cells indicated that p300ΔC-1087 suppresses an NF-κB gene expression program and activates a MYC gene expression program in RC-K8 cells. Bioinformatic analysis demonstrated that cancer cell lines— regardless of tissue type—with truncating p300 mutations have altered expression of a MYC target gene set as compared to cancer cell lines with wild-type p300/CBP. Taken together, this research indicates that p300 truncations contribute to cell growth in DLBCL by modifying the transcriptional output of two lymphoid cell-specific oncoproteins, NF- κB and MYC, to optimal levels and suggests that p300 truncating mutations similarly modify the activity of oncogenic drivers in other cancer cell types. Based on this work, p300 truncation is proposed to represent a new class of oncogenic mutation that serves to optimize the activity of context-specific oncogenic transcription factors, and it is suggested that such oncogenic mutations be termed “cancer modifying” mutations.2017-09-30T00:00:00

The landscape of somatic copy-number alteration across human cancers

A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here, we report high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κB pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types

The landscape of somatic copy-number alteration across human cancers

available in PMC 2010 August 18.A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109038))National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109467)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA085859)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA 098101)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, K08CA122833