Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia.

Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is an aggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. As a result, clinical outcome remains poor for the majority of patients, with overall long-term survival in the region of 20-30%. Recent successes in characterizing the genetic landscape of AML have highlighted that, despite its heterogeneity, many cases of AML carry recurrent mutations in genes encoding epigenetic regulators. Transcriptional dysregulation and altered epigenetic function have therefore emerged as exciting areas in AML research and it is becoming increasingly clear that epigenetic dysfunction is central to leukemogenesis in AML. This has subsequently paved the way for the development of epigenetically targeted therapies. In this review, we will discuss the most recent advances in our understanding of the role of epigenetic dysregulation in AML pathobiology. We will particularly focus on those altered epigenetic programs that have been shown to be central to the development and maintenance of AML in preclinical models. We will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that these novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.We would like to thank all the members of the Huntly laboratory and our funders Leukaemia Lymphoma Research, Kay Kendall Leukaemia fund, the Medical Research Council UK, the Wellcome Trust, the Cambridge NIHR Biomedical Research Centre, Leukemia & Lymphoma Society US, the Academy of Medical Sciences UK and Lady Tata Memorial Trust. We apologise to writers whose work we have failed to cite due to space constraints.This is the author accepted manuscript. The final version is available via SAGE at http://dx.doi.org/10.1177/204062071557761

Classroom enrichment through children's specialties.

Thesis (Ed.M.)--Boston Universit

Independence of epigenetic and genetic diversity in AML.

A new study provides the first insights into epigenetic heterogeneity in AML. The study highlights a striking independence of genetic and epigenetic variation, and links the kinetics of epigenetic change to clinical outcome.Medical Research Council, Wellcome Trust, Mildred-Scheel OrganisationThis is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nm.413

Deletions of the derivative chromosome 9 occur at the time of the Philadelphia translocation and provide a powerful and independent prognostic indicator in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph+ metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P = .0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P = .057 and P = .034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. The prognostic significance of deletion status should now be studied prospectively and, if confirmed, should be incorporated into management decisions and the analysis of clinical trials. (C) 2001 by The American Society of Hematology

Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5(+/-) leukemia.

BACKGROUND: B-cell precursor acute lymphoblastic leukemia (B-ALL) is amongst the leading causes of childhood cancer-related mortality. Its most common chromosomal aberration is the ETV6-RUNX1 fusion gene, with ~25% of ETV6-RUNX1 patients also carrying PAX5 alterations. METHODS: We have recreated this mutation background by inter-crossing Etv6-RUNX1 (Etv6 (RUNX1-SB)) and Pax5(+/-) mice and performed an in vivo analysis to find driver genes using Sleeping Beauty transposon-mediated mutagenesis and also exome sequencing. RESULTS: Combination of Etv6-RUNX1 and Pax5(+/-) alleles generated a transplantable B220 + CD19+ B-ALL with a significant disease incidence. RNA-seq analysis showed a gene expression pattern consistent with arrest at the pre-B stage. Analysis of the transposon common insertion sites identified genes involved in B-cell development (Zfp423) and the JAK/STAT signaling pathway (Jak1, Stat5 and Il2rb), while exome sequencing revealed somatic hotspot mutations in Jak1 and Jak3 at residues analogous to those mutated in human leukemias, and also mutation of Trp53. CONCLUSIONS: Powerful synergies exists in our model suggesting STAT pathway activation and mutation of Trp53 are potent drivers of B-ALL in the context of Etv6-RUNX1;Pax5(+/-)

Remarks of Huntly Collins

Remarks by Huntly Collins , assistant professor of communication, as part of a symposium on Lasallian higher education in Philadelphia

Overview of the uptake and implementation of non-medical prescribing in Wales: a national survey

Objectives To identify (1) the non-medical healthcare professionals in Wales qualified to prescribe medicines (including job title, employer, where the prescribing qualification is used, care setting and service provided); (2) the mode of prescribing used by these healthcare professionals, the frequency with which medicines are prescribed and the different ways in which the prescribing qualification is used; and (3) the safety and clinical governance systems within which these healthcare professionals practise. Design National questionnaire survey. Setting All three National Health Service (NHS) Trusts and seven Health Boards (HB) in Wales. Participants Non-medical prescribers. Results 379 (63%) participants responded to the survey. Most of these prescribers (41.1%) were specialist nurses who work in a variety of healthcare settings (primarily in secondary care) within each HB/NHS Trust, and regularly use independent prescribing to prescribe for a broad range of conditions. Nearly a quarter of the sample (22%) reported that prior to undertaking the prescribing programme, they had completed master’s level specialist training and 65.5% had 5 years qualified experience. Over half (55.8%) reported that there were plans to increase non-medical prescriber numbers within the team in which they worked. Only 7.1% reported they did not prescribe and the median number of items prescribed per week was between 21 and 30. Nearly all (87.8%) of the sample reported that they perceived prescribing to have ensured better use of their skills and 91.5% indicated that they believed it had improved the quality of care they were able to provide. Conclusion Non-medical prescribing has been implemented across the whole of Wales; however, its uptake within HBs and NHS Trusts has been inconsistent, and it has not been considered across all services, particularly those in primary care. Opportunities therefore exist to share learning across organisations

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