CREBBP mutations in relapsed acute lymphoblastic leukaemia

Abstract

Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biologic determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways 1, 2, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse3. However, detailed analysis of sequence mutations in ALL has not been performed. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosisrelapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase (HAT) CREB-binding protein (CBP) 4 . The mutations were either present NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2011 September 10. at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the HAT domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.Acute lymphoblastic leukaemia (ALL) is the commonest childhood malignancy 5 , and is a leading cause of cancer-related death in young people. Several structural chromosomal alterations in ALL, including rearrangement of MLL and the Philadelphia chromosome 6 are associated with a high risk of treatment failure and relapse. However, many ALL cases that fail therapy lack these alterations, and the biologic basis of treatment failure in these cases is poorly understood. Genome-wide profiling of ALL has identified multiple recurring submicroscopic genetic alterations targeting lymphoid development, cell cycle regulation, tumour suppression and apoptosis 1,2 , and has identified genetic alterations that predict a high risk of relapse, including deletion of IKZF1 (IKAROS) 7, 8. Moreover, profiling of structural DNA alterations in matched diagnosis and relapse samples has demonstrated that in the majority of cases there are substant...

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

“…CREBBP mutations, including those targeting arginine-1408/1446, impair global histone acetylation (21). Nevertheless, the ultimate phenotypic consequences of these and other CMG mutations remain poorly defined.…”

“…S9). This amino acid contacts the substrate of CREBBP, resulting in decreased histone acetylation (21), and other recurrently mutated residues in the lysine acetyltransferase domain also reside within the substratebinding pocket (SI Appendix, Fig. S9).…”

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

“…Both gain-of-function mutations in Ras isoforms (H-Ras, K-Ras, or N-Ras) and loss-of-function mutations that directly activate Ras/MAPK signaling have been identified in human and murine leukemias and lymphomas, many of which overexpress Myc. 14,16,24 In addition, analysis of human B-cell malignancies showed a frequent increase in the copy number of genomic regions that contain Ras pathway components. 25 However, none of the studies examined whether endogenous Ras pathway signaling contributes to Myc-induced lymphoma development or how Ras pathway signaling impacts Myc-driven tumorigenesis.…”

Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637)

“…To that end, α-methyl benzyl compounds 15 and 16 were prepared to introduce a conformational constraint to 14, which reduced BRD4 activity in both diastereomers but failed to improve potency against CBP. Subsequent efforts to modify the N-benzyl ring (17), extend the α-substituent (18), or cyclize the amide substituent (19) did not improve CBP affinity, reduced selectivity over BRD4, or both. Anilide derivatives such as 20 demonstrated the possibility of identifying potent CBP inhibitors, but this subseries was not pursued because of concern about extended conjugation and lower solubility (Table 2).…”