BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms.

Small molecule inhibition of the BET family of proteins, which bind acetylated lysines within histones, has been shown to have a marked therapeutic benefit in pre-clinical models of mixed lineage leukemia (MLL) fusion protein-driven leukemias. Here, we report that I-BET151, a highly specific BET family bromodomain inhibitor, leads to growth inhibition in a human erythroleukemic (HEL) cell line as well as in erythroid precursors isolated from polycythemia vera patients. One of the genes most highly downregulated by I-BET151 was LMO2, an important oncogenic regulator of hematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon Janus kinase 2 (JAK2) kinase activity in HEL cells. Here, we show that the transcriptional changes induced by a JAK2 inhibitor (TG101209) and I-BET151 in HEL cells are significantly over-lapping, suggesting a common pathway of action. We generated JAK2 inhibitor resistant HEL cells and showed that these retain sensitivity to I-BET151. These data highlight I-BET151 as a potential alternative treatment against myeloproliferative neoplasms driven by constitutively active JAK2 kinase.The Kouzarides laboratory was supported by Cancer Research UK, Leukaemia and Lymphoma Research, GlaxoSmithKline and BBSRC. The Green laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. The Gottgens laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. The Huntly laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. M. A Dawson, E Cannizzaro and M. Wiese are funded by the Wellcome Trust Beit Fellowship.This is the accepted manuscript version of the article. The final version is available from http://www.nature.com/leu/journal/v28/n1/full/leu2013234a.html

HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias

The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2

Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia

Epigenetic mechanisms such as DNA hypermethylation and modifications of histone amino acids are known to play an important role in the control of gene expression both in normal human development and tumorigenesis. Hypermethylation of CpG islands within promoter regions of tumor suppressor genes is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of human cancer. Inter-α-trypsine inhibitors (ITIs) are a family of serine protease inhibitors consisting of one light chain (bikunin) and two heavy chains (ITI heavy chains, ITIHs). ITIHs stabilize the extracellular matrix (ECM) by interacting with hyaluronic acid, which is a major ECM component. Hypermethylation in the upstream region of the promoter-associated CpG island of ITIH5, the most recently described member of the ITIH family, has been previously detected in breast cancer and was associated with an adverse outcome. In this study, we determined the DNA methylation status of the promoter region near the transcription start site of the ITIH5 tumor suppressor gene in leukemia cell lines and primary samples from patients with acute myeloid leukemia (AML) as well as the potential use of demethylating agents to restore a demethylated state of the promoter. Aberrant ITIH5 promoter hypermethylation occurred in 15 of 104 (14.4%) diagnostic AML samples. There were no statistically significant correlations between the ITIH5 methylation status and clinical prognostic parameters. Our results indicate that aberrant ITIH5 promoter hypermethylation is a novel epigenetic event in AML

Työvoiman ikääntyminen ja ikäjohtaminen Suomen kunnissa asiakirja-analyysi kuntien strategioista

In response to a sharp decline in recreational fishing participation in Queensland, Australia, I sought to identify constraints experienced by fishers in Queensland and understand how demographic variables, fishing participation variables, and fishing motivations influence the amount and type of constraints experienced. In a survey of Queensland recreational fishers, 70% reported experiencing constraints-predominantly lack of time, crowding, unavailability of facilities, and costs associated with fishing. Fishers with higher incomes, fishers with higher centrality of fishing to lifestyle, fishers who placed higher importance on motivations related to catching fish and relaxation, and fishers who were male were more likely to experience constraints. With the exception of gender, variables found to have a significant effect on the presence of constraints also had a significant influence on the types of constraints experienced. Results provide insight into factors affecting recreational fishing participation in Queensland; however, additional research-particularly with recent fishing drop-outs-is needed to fully understand recent declines in fishing participation

EHA evaluation of the ESMO—Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies

Objective: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology—Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. Results: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. Conclusions: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials

A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as $\textit{DOT1L}$, $\textit{BCL2}$, and $\textit{MEN1}$, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose $\textit{KAT2A}$ as a candidate for downstream study. $\textit{KAT2A}$ inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.This work was funded by the Kay Kendall Leukaemia Fund (KKLF) and the Wellcome Trust (WT098051). G.S.V. is funded by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA) and work in his laboratory is funded by Bloodwise. C.P. is funded by a Kay Kendall Leukaemia Fund Intermediate Fellowship (KKL888)

The double PHD finger domain of MOZ/MYST3 induces α-helical structure of the histone H3 tail to facilitate acetylation and methylation sampling and modification

Histone tail modifications control many nuclear processes by dictating the dynamic exchange of regulatory proteins on chromatin. Here we report novel insights into histone H3 tail structure in complex with the double PHD finger (DPF) of the lysine acetyltransferase MOZ/MYST3/KAT6A. In addition to sampling H3 and H4 modification status, we show that the DPF cooperates with the MYST domain to promote H3K9 and H3K14 acetylation, although not if H3K4 is trimethylated. Four crystal structures of an extended DPF alone and in complex with unmodified or acetylated forms of the H3 tail reveal the molecular basis of crosstalk between H3K4me3 and H3K14ac. We show for the first time that MOZ DPF induces α-helical conformation of H3K4-T11, revealing a unique mode of H3 recognition. The helical structure facilitates sampling of H3K4 methylation status, and proffers H3K9 and other residues for modification. Additionally, we show that a conserved double glycine hinge flanking the H3 tail helix is required for a conformational change enabling docking of H3K14ac with the DPF. In summary, our data provide the first observations of extensive helical structure in a histone tail, revealing the inherent ability of the H3 tail to adopt alternate conformations in complex with chromatin regulators

UK Space Agency ``Mars Utah Rover Field Investigation 2016'' (MURFI 2016): Overview of Mission, Aims, and Progress

The Mars Utah Rover Field Investigation “MURFI 2016” is a Mars Rover field analogue mission run by the UK Space Agency (UKSA) in collaboration with the Canadian Space Agency (CSA). MURFI 2016 took place between 22nd October and 13th November 2016 and consisted of a field team including an instrumented Rover platform, at the field site near Hanksville (Utah, USA), and an ‘Operations Team’ based in the Mission Control Centre (MOC) at the Harwell Campus near Oxford in the UK.The field site was chosen based on the collaboration with the CSA and its Mars-like local geology. It was used by the CSA in 2015 for Mars Rover trials, and in 2016, several teams used the site, each with their own designated working areas. The two main aims of MURFI 2016 were (i) to develop logistical and leadership experience in running field trials within the UKSA, and (ii) to provide members of the Mars Science community with Rover Operations experience, and hence to build expertise that could be used in the 2020 ExoMars Rover mission, or other future Rover missions. Because MURFI 2016 was the first solely UKSA-led Rover analogue trial, the most important objective was to learn how to best implement Rover trials in general. This included aspects of planning, logistics, field safety, MOC setup and support, communications, person management and science team development. Some aspects were based on past experience from previous trials but the focus was on ‘learning through experience’ - especially in terms of the Operations Team, who each took on a variety of roles during the mission

The 2016 UK Space Agency Mars Utah Rover Field Investigation (MURFI)

The 2016 Mars Utah Rover Field Investigation (MURFI) was a Mars rover field trial run by the UK Space Agency in association with the Canadian Space Agency's 2015/2016 Mars Sample Return Analogue Deployment mission. MURFI had over 50 participants from 15 different institutions around the UK and abroad. The objectives of MURFI were to develop experience and leadership within the UK in running future rover field trials; to prepare the UK planetary community for involvement in the European Space Agency/Roscosmos ExoMars 2020 rover mission; and to assess how ExoMars operations may differ from previous rover missions. Hence, the wider MURFI trial included a ten-day (or ten-‘sol’) ExoMars rover-like simulation. This comprised an operations team and control centre in the UK, and a rover platform in Utah, equipped with instruments to emulate the ExoMars rovers remote sensing and analytical suite. The operations team operated in ‘blind mode’, where the only available data came from the rover instruments, and daily tactical planning was performed under strict time constraints to simulate real communications windows. The designated science goal of the MURFI ExoMars rover-like simulation was to locate in-situ bedrock, at a site suitable for sub-surface core-sampling, in order to detect signs of ancient life. Prior to “landing”, the only information available to the operations team were Mars-equivalent satellite remote sensing data, which were used for both geologic and hazard (e.g., slopes, loose soil) characterisation of the area. During each sol of the mission, the operations team sent driving instructions and imaging/analysis targeting commands, which were then enacted by the field team and rover-controllers in Utah. During the ten-sol mission, the rover drove over 100 m and obtained hundreds of images and supporting observations, allowing the operations team to build up geologic hypotheses for the local area and select possible drilling locations. On sol 9, the team obtained a subsurface core sample that was then analyzed by the Raman spectrometer. Following the conclusion of the ExoMars-like component of MURFI, the operations and field team came together to evaluate the successes and failures of the mission, and discuss lessons learnt for ExoMars rover and future field trials. Key outcomes relevant to ExoMars rover included a key recognition of the importance of field trials for (i) understanding how to operate the ExoMars rover instruments as a suite, (ii) building an operations planning team that can work well together under strict time-limited pressure, (iii) developing new processes and workflows relevant to the ExoMars rover, (iv) understanding the limits and benefits of satellite mapping and (v) practicing efficient geological interpretation of outcrops and landscapes from rover-based data, by comparing the outcomes of the simulated mission with post-trial, in-situ field observations. In addition, MURFI was perceived by all who participated as a vital learning experience, especially for early and mid-career members of the team, and also demonstrated the UK capability of implementing a large rover field trial. The lessons learnt from MURFI are therefore relevant both to ExoMars rover, and to future rover field trials