39 research outputs found

    The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.

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    Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.Funding in the Huntly laboratory comes from Cancer Research UK, Leukemia Lymphoma Research, the Kay Kendal Leukemia Fund, the Leukemia lymphoma Society of America, the Wellcome Trust, The Medical Research Council and an NIHR Cambridge Biomedical Research Centre grant. Patient samples were processed in the Cambridge Blood and Stem Cell Biobank.This is the author accepted manuscript. The final version is available via NPG at http://dx.doi.org/10.1038/onc.2015.9

    Genome-Wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia

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    Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer

    Baltic Salmon, Salmo salar, from Swedish River Lule Älv Is More Resistant to Furunculosis Compared to Rainbow Trout

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    BACKGROUND: Furunculosis, caused by Aeromonas salmonicida, continues to be a major health problem for the growing salmonid aquaculture. Despite effective vaccination programs regular outbreaks occur at the fish farms calling for repeated antibiotic treatment. We hypothesized that a difference in natural susceptibility to this disease might exist between Baltic salmon and the widely used rainbow trout. STUDY DESIGN: A cohabitation challenge model was applied to investigate the relative susceptibility to infection with A. salmonicida in rainbow trout and Baltic salmon. The course of infection was monitored daily over a 30-day period post challenge and the results were summarized in mortality curves. RESULTS: A. salmonicida was recovered from mortalities during the entire test period. At day 30 the survival was 6.2% and 34.0% for rainbow trout and Baltic salmon, respectively. Significant differences in susceptibility to A. salmonicida were demonstrated between the two salmonids and hazard ratio estimation between rainbow trout and Baltic salmon showed a 3.36 higher risk of dying from the infection in the former. CONCLUSION: The finding that Baltic salmon carries a high level of natural resistance to furunculosis might raise new possibilities for salmonid aquaculture in terms of minimizing disease outbreaks and the use of antibiotics

    Spatial Patterns in Herbivory on a Coral Reef Are Influenced by Structural Complexity but Not by Algal Traits

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    Background: Patterns of herbivory can alter the spatial structure of ecosystems, with important consequences for ecosystem functions and biodiversity. While the factors that drive spatial patterns in herbivory in terrestrial systems are well established, comparatively less is known about what influences the distribution of herbivory in coral reefs. Methodology and Principal Findings: We quantified spatial patterns of macroalgal consumption in a cross-section of Ningaloo Reef (Western Australia). We used a combination of descriptive and experimental approaches to assess the influence of multiple macroalgal traits and structural complexity in establishing the observed spatial patterns in macroalgal herbivory, and to identify potential feedback mechanisms between herbivory and macroalgal nutritional quality. Spatial patterns in macroalgal consumption were best explained by differences in structural complexity among habitats. The biomass of herbivorous fish, and rates of herbivory were always greater in the structurally-complex coral-dominated outer reef and reef flat habitats, which were also characterised by high biomass of herbivorous fish, low cover and biomass of macroalgae and the presence of unpalatable algae species. Macroalgal consumption decreased to undetectable levels within 75 m of structurally-complex reef habitat, and algae were most abundant in the structurally-simple lagoon habitats, which were also characterised by the presence of the most palatable algae species. In contrast to terrestrial ecosystems, herbivory patterns were not influenced by the distribution, productivity or nutritional quality of resources (macroalgae), and we found no evidence of a positive feedback between macroalgal consumption and the nitrogen content of algae. Significance: This study highlights the importance of seascape-scale patterns in structural complexity in determining spatial patterns of macroalgal consumption by fish. Given the importance of herbivory in maintaining the ability of coral reefs to reorganise and retain ecosystem functions following disturbance, structural complexity emerges as a critical feature that is essential for the healthy functioning of these ecosystems

    Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation

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    We sought to understand the genesis of the t(9;22) by characterizing genomic breakpoints in chronic myeloid leukemia (CML) and BCR–ABL-positive acute lymphoblastic leukemia (ALL). BCR–ABL breakpoints were identified in p190 ALL (n=25), p210 ALL (n=25) and p210 CML (n=32); reciprocal breakpoints were identified in 54 cases. No evidence for significant clustering and no association with sequence motifs was found except for a breakpoint deficit in repeat regions within BCR for p210 cases. Comparison of reciprocal breakpoints, however, showed differences in the patterns of deletion/insertions between p190 and p210. To explore the possibility that recombinase-activating gene (RAG) activity might be involved in ALL, we performed extra-chromosomal recombination assays for cases with breakpoints close to potential cryptic recombination signal sequence (cRSS) sites. Of 13 ALL cases tested, 1/10 with p190 and 1/3 with p210 precisely recapitulated the forward BCR–ABL breakpoint and 1/10 with p190 precisely recapitulated the reciprocal breakpoint. In contrast, neither of the p210 CMLs tested showed functional cRSSs. Thus, although the t(9;22) does not arise from aberrant variable (V), joining (J) and diversity (D) (V(D)J) recombination, our data suggest that in a subset of ALL cases RAG might create one of the initiating double-strand breaks.<br/

    Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

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    RAF kinase inhibitor protein (RKIP) is a negative regulator of the RAS-mitogen-activated protein kinase/extracellular signal-regulated kinase signaling cascade. We investigated its role in acute myeloid leukemia (AML), an aggressive malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Western blot analysis revealed loss of RKIP expression in 19/103 (18%) primary AML samples and 4/17 (24%) AML cell lines but not in 10 CD34+ HSPC specimens. In in-vitro experiments with myeloid cell lines, RKIP overexpression inhibited cellular proliferation and colony formation in soft agar. Analysis of two cohorts with 103 and 285 AML patients, respectively, established a correlation of decreased RKIP expression with monocytic phenotypes. RKIP loss was associated with RAS mutations and in transformation assays, RKIP decreased the oncogenic potential of mutant RAS. Loss of RKIP further related to a significantly longer relapse-free survival and overall survival in uni- and multivariate analyses. Our data show that RKIP is frequently lost in AML and correlates with monocytic phenotypes and mutations in RAS. RKIP inhibits proliferation and transformation of myeloid cells and decreases transformation induced by mutant RAS. Finally, loss of RKIP seems to be a favorable prognostic parameter in patients with AML
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