Researchers claim findings point to potential utility of histone deacetylase inhibitors against relevant malignancies.
Two independent studies have identified a high incidence of mutations in the related histone acetyltransferase genes CREBBP and EP300 in two subtypes of B cell lymphoma and also in acute lymphoblastic leukemia. Both Kat3 acetyltransferase family proteins act as transcriptional co-activators for a large number of DNA-binding transcription factors involved in multiple signaling and developmental pathways.
The two sets of authors report their research in the same issue of Nature. They suggest the findings point to the potential utility of drugs targeting acetylation/deacetylation mechanisms in the treatment of such cancers.
Columbia University’s Laura Pasqualucci, Ph.D., and colleagues carried out an integrated next-generation whole-exome sequencing analysis of seven cases of diffuse large B cell lymphoma (DLBCL) and genome-wide high-density SNP array analysis of 72 DLBCL cases. They found that among the gene regions that have been independently validated in the disease, the most commonly involved regions identified harbored the acetyltransferase genes CREBBP and EP300.
The team subsequently re-sequenced the entire CREBBP coding exons in 134 DLBCL samples representative of major phenotypic subtypes. Of the 34 variants they found in 30 samples, 50% were predicted to cause the elimination or truncation of the HAT domain. The remaining mutations were also expected to be functionally detrimental to the CREBBP protein. Overall, 29% of all DLBCL patients harbored genomic alterations.
More specifically, mutations were found in 41.5% of GCB-DLBCL (germinal center B-cell-like DLBCL) cases and 17% of ABC-DLBCL (activated B-cell-like DLBCL) “but not in other lymphoma types, suggesting a specific role in the pathogenesis of these two diseases,” the Columbia University researchers note.
Given the significant structural and functional similarities between CREBBP and EP300, the team then went on to see whether structural EP300 mutations were also present in the same cancers. Sequence variants leading to potentially functional changes in the protein were found in 10% of DLBCL and 8.7% of follicular lymphoma samples but were almost absent in other types of B-NHL.
Overall about 39% of all DLBCL cases and at least 41% of follicular lymphoma cases displayed structural alterations of the two KAT3 family genes, and a large proportion of these cases had reduced expression levels of the two proteins. “These results indicate that inactivation of CREBBP/EP300 represents a common event in the two most frequent forms of B-NHL, namely follicular lymphoma and DLBCL,” the authors write. “Considering their almost total absence in solid tumours and the finding of recurrent mutations in B-cell acute lymphoblastic leukemia, our results point to a specific role for CREBBP/EP300 inactivation in the pathogenesis of malignancies derived from B-lymphocytes. Overall, CREBBP/EP300 lesions are among the most frequent structural alterations yet detected in follicular lymphoma and DLBCL, thus representing an important feature of the pathogenesis of these common diseases.”
They suggest the data has important therapeutic implications with respect to the potential use of histone deacetylase inhibitors as anticancer drugs. “The findings of this study suggest that the use of histone deacetylase inhibitors has a rational basis in B-NHL because it may contribute to re-establishing physiologic acetylation levels.” The Columbia University-led findings are published in a paper titled, “Inactivating mutations of acetyltransferase genes in B-cell lymphoma.”
In the same issue of Nature, a team led by researchers at St. Jude Children’s Research Hospital in Memphis, TN, reported on their study looking for mutations in genes that might correlate with relapse in patients with acute lymphoblastic leukemia (ALL). The team, led by Charles G. Mullighan and Jinghui Zhang, resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. They then carried out an analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukemia cases that did not relapse.
The analysis identified sequence or deletion mutations in CREBBP in 18.3% of relapse cases. Conversely, “CREBBP alterations in cases of childhood acute leukemia that did not relapse were rare, with only one additional CREBBP mutation identified in 200 AML and ALL cases,” the researchers note.
Importantly, the CREBBP mutations were either present at diagnosis or acquired at relapse and were associated with impaired histone acetylation and transcriptional regulation of CREBBP targets, the team discovered. “Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy.”
The team subsequently confirmed the adverse effects of CREBBP mutations on histone acetylation and other biochemical processes in mouse models. They suggests that the high frequency of CREBBP mutations in relapsed ALL, combined with the persistence, re-duplication, or emergence of mutations from diagnosis to relapse and the location of the mutations in key CREBBP functional domains suggest that the gene alterations not only impair CREBBP function but also influence treatment responsiveness.
“These results, together with those of Pasqualucci et al. identifying a high frequency of CREBBP and EP300 mutations in diffuse large B-cell and follicular lymphoma, also identify CREBBP and EP300 as new targets of recurring mutation in a range of lymphoid malignancies,” concludes the group from St. Jude Children’s Research Hospital.
“The observation that the CREBBP mutations impair regulation of glucocorticoid-responsive genes and that the mutations are selected for at relapse suggests that these alterations may influence response to therapy and the likelihood of relapse. These results are also of clinical relevance because they suggest that therapeutic approaches directed at modulating protein acetylation may be useful in high-risk ALL, particularly as HDAC inhibitors may induce apoptosis in glucocorticoid-resistant leukemic cells.”
Details appear in a paper is titled “CREBBP mutations in relapsed acute lymphoblastic Leukemia.”