Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

Cre recombinase expression cooperates with homozygous FLT3 internal tandem duplication knockin mouse model to induce acute myeloid leukemia.

Murine models offer a valuable tool to recapitulate genetically defined subtypes of AML, and to assess the potential of compound mutations and clonal evolution during disease progression. This is of particular importance for difficult to treat leukemias such as FLT3 internal tandem duplication (ITD) positive AML. While conditional gene targeting by Cre recombinase is a powerful technology that has revolutionized biomedical research, consequences of Cre expression such as lack of fidelity, toxicity or off-target effects need to be taken into consideration. We report on a transgenic murine model of FLT3-ITD induced disease, where Cre recombinase expression alone, and in the absence of a conditional allele, gives rise to an aggressive leukemia phenotype. Here, expression of various Cre recombinases leads to polyclonal expansion of FLT3ITD/ITD progenitor cells, induction of a differentiation block and activation of Myc-dependent gene expression programs. Our report is intended to alert the scientific community of potential risks associated with using this specific mouse model and of unexpected effects of Cre expression when investigating cooperative oncogenic mutations in murine models of cancer.

Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia.

Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G1S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.

The Role of an Anti-Inflammatory Diet in Conjunction to COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), otherwise known as COVID-19, has challenged healthcare systems at an international level. COVID-19 suppresses the immune system by causing a systemic inflammatory response, also known as cytokine release syndrome, leaving COVID-19 patients with high levels of proinflammatory cytokines and chemokines. Nutrition's function in the respiratory and immune systems has been investigated in much research, and its significance cannot be overstated, as the nutritional status of patients has been shown to be directly connected with the severity of the disease. Key dietary components such as vitamin C, D, omega-3 fatty acids, and zinc have shown potential in their anti-inflammatory effects, as well as the famous Mediterranean diet. This review aims to discuss the use of anti-inflammatory dietary approaches to prevent Sars-CoV-2 or lessen COVID-19 effects.

Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.

The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.

Development and evaluation of an educational game to support pharmacy students.

INTRODUCTION: United Kingdom pharmacy students need to efficiently navigate the British National Formulary (BNF), a standard medicines reference source. "Pharmacy Challenge" is a web-based prototype game based on the BNF. This research aimed to evaluate the game in terms of design, content, and impact on students' performance and confidence. METHODS: Evaluation was comprised of three phases: implementation, perception, and impact. Game design and evaluation methods were modelled using adapted elements of the Relevance Embedding Translation Adaption Immersion and Naturalisation framework. Qualitative and quantitative questionnaires were utilised to assess students' perceptions of the game and its role in their education and to evaluate changes in confidence and performance after playing the game. Quizzes were developed to determine changes in performance. RESULTS: The questionnaire evaluation (n = 152) found students' confidence increased significantly (p < .05) in speed of using, knowledge of BNF sections, extracting information, and knowing where to look for the answer. Most students (88%) felt they had learnt something new and 86% felt that it reinforced their learning. A significant (p < .05) increase in pre- and post- BNF quiz marks was observed. CONCLUSIONS: Statistically significant improvement in students' perceived confidence was noted. The study identified design elements such as the need for a simple interface to encourage engagement. The prototype has undergone a design transformation based on the feedback provided and is now released under the name "DOSE" with a bank of 300 questions, improved graphics, a leadership board, and medals.

Attenuated Acceleration to Leukemia after Ezh2 Loss in Nup98-HoxD13 (NHD13) Myelodysplastic Syndrome.

Supplemental Digital Content is available in the text.

Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation.

Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a-/- Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.

How unique is pure erythroid leukaemia? A retrospective analysis of seven cases and review of the literature.

AIMS: Pure erythroid leukaemia (PEL) is a rare subtype of acute myeloid leukaemia (AML) and its clinicopathological features are not well-defined. The aim of this study was to describe the immunophenotypic, cytogenetic and clinical features of PEL and to compare these with cases of AML with ≥ 50% erythroblasts. METHODS: Cases of PEL according to WHO morphological criteria diagnosed at three institutions from 1997 to 2013 were included. A comparison cohort comprised of AML with ≥ 50% erythroblasts. The clinical, histopathology, immunophenotypic and cytogenetic features of cases were analysed. We also reviewed the existing literature on PEL, and combined our cohort with previously reported cases of PEL in a pooled analysis. RESULTS: There were seven cases of PEL diagnosed at our institutions. There was a high incidence of either prior chemoradiotherapy exposure or evolution from pre-existing myelodysplastic syndrome (MDS) (71%). The leukaemic blasts frequently expressed glycophorin C (100%), CD117 (83%) and were myeloperoxidase negative (83%). Complex karyotypes were present in 83% of cases. Median overall survival was 2.9 months. Compared with AML with ≥ 50% erythroblasts, cases of PEL demonstrated a higher incidence of adverse-risk cytogenetics (p=0.01) and prior exposure to chemoradiotherapy (p=0.01). CONCLUSIONS: PEL appears to be a unique entity that is often secondary or therapy related, commonly features a complex karyotype and has a poor prognosis. It is morphologically and immunophenotypically distinct from other cases of AML with erythroid hyperplasia.

Suspected acute exacerbation of idiopathic pulmonary fibrosis associated with interferon alpha therapy for hepatitis C: case report.

Interferon alpha (IFNα) has immune stimulatory actions implicated in its pulmonary toxicities. We describe deterioration of idiopathic pulmonary fibrosis (IPF) associated with IFNα treatment for chronic hepatitis C in a 58 year old woman culminating in a fatal suspected acute exacerbation of IPF (AE-IPF). Caution should be exercised in the use of IFNα in subjects with concomitant IPF given its known immunostimulatory effects and possible role in this suspected AE-IPF.

Primate archaeology.

All modern humans use tools to overcome limitations of our anatomy and to make difficult tasks easier. However, if tool use is such an advantage, we may ask why it is not evolved to the same degree in other species. To answer this question, we need to bring a long-term perspective to the material record of other members of our own order, the Primates.