RNA binding proteins in hematopoiesis and hematological malignancy.

RNA binding proteins (RBPs) regulate fundamental processes such as differentiation and self-renewal by enabling the dynamic control of protein abundance or isoforms, or through the regulation of non-coding RNA. RBPs are increasingly appreciated as being essential for normal hematopoiesis and they are understood to play fundamental roles in hematological malignancies by acting as oncogenes or tumor suppressors. Alternative splicing has been shown to play roles in the development of specific hematopoietic lineages and sequence specific mutations in RBPs lead to dysregulated splicing in myeloid and lymphoid leukemias. RBPs that regulate translation contribute to the development and function of hematological lineages, act as nodes for the action of multiple signaling pathways and contribute to hematological malignancies. These insights broaden our mechanistic understanding of the molecular regulation of hematopoiesis and offer opportunities to develop disease biomarkers and new therapeutic modalities.We thank the Medical Research Council, The Biotechnology and Biological Sciences Research Council BBS/E/B/000C0428, Bloodwise, Cancer Research Therapeutics and Wellcome for funding research in the author’s laboratories

RNA helicase EIF4A1-mediated translation is essential for the GC response

EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5' untranslated regions. However, very little is known of their roles in nonmalignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells, we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. After B cell activation in vitro, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression, and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable, whereas inhibition of EIF4A1 and EIF4A2 by Hippuristanol treatment induces cell death.</p

RNA helicase EIF4A1-mediated translation is essential for the GC response

EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5' untranslated regions. However, very little is known of their roles in nonmalignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells, we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. After B cell activation in vitro, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression, and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable, whereas inhibition of EIF4A1 and EIF4A2 by Hippuristanol treatment induces cell death.</p

The Arctic and the UK: Climate, research and engagement

• The Arctic has warmed by around 2°C since 1850, approximately double the global average. Even if the Paris Agreement successfully limits global warming to a further 0.5°C, the Arctic is expected to warm by at least another 1°C. • The United Kingdom’s (UK) weather is linked to conditions in the European Arctic. For example, high atmospheric pressure in the Nordic Seas divert damaging storms across the UK and mainland Europe, with the potential to cause societal disruption from flooding. • It is possible, although presently unconfirmed, that alterations in Arctic conditions provoked the ‘Beast from the East’ winter storm in 2018. • Scientists need to take observations and improve their understanding of climatic processes in the Nordic Seas and the Arctic Ocean to fill gaps in knowledge about the links between the Arctic climate and the UK’s weather; a risk identified by the Intergovernmental Panel on Climate Change (IPCC). • The UK has significant research expertise and experience to understand how global warming will change the Arctic’s environment and affect the UK. • This strength, allied with the capabilities of the UK’s new polar research ship the RRS Sir David Attenborough, warrants an integrated programme of research, including advanced numerical modelling, to improve predictions of future extreme weather events. • Such a programme must acknowledge that the Arctic is politically an increasingly congested and contested space. It should be designed in collaboration with key Arctic and near-Arctic nations to increase the UK’s influence and abilit

The RNA-binding protein PTBP1 is necessary for B cell selection in germinal centers.

Antibody affinity maturation occurs in germinal centers (GCs), where B cells cycle between the light zone (LZ) and the dark zone. In the LZ, GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from helper T cells, which promotes their rapid proliferation. Here we found that the RNA-binding protein PTBP1 was needed for the progression of GC B cells through late S phase of the cell cycle and for affinity maturation. PTBP1 was required for proper expression of the c-MYC-dependent gene program induced in GC B cells receiving T cell help and directly regulated the alternative splicing and abundance of transcripts that are increased during positive selection to promote proliferation

Incidence and prevalence of patellofemoral pain: a systematic review and meta-analysis

Background: Patellofemoral pain is considered one of the most common forms of knee pain, affecting adults, adolescents, and physically active populations. Inconsistencies in reported incidence and prevalence exist and in relation to the allocation of healthcare and research funding, there is a clear need to accurately understand the epidemiology of patellofemoral pain. Methods: An electronic database search was conducted, as well as grey literature databases, from inception to June 2017. Two authors independently selected studies, extracted data and appraised methodological quality. If heterogeneous, data were analysed descriptively. Where studies were homogeneous, data were pooled through a meta-analysis. Results: 23 studies were included. Annual prevalence for patellofemoral pain in the general population was reported as 22.7%, and adolescents as 28.9%. Incidence rates in military recruits ranged from 9.7 – 571.4/1,000 person-years, amateur runners in the general population at 1080.5/1,000 person-years and adolescents amateur athletes 5.1% - 14.9% over 1 season. One study reported point prevalence within military populations as 13.5%. The pooled estimate for point prevalence in adolescents was 7.2% (95% Confidence Interval: 6.3% - 8.3%), and in female only adolescent athletes was 22.7% (95% Confidence Interval 17.4% - 28.0%). Conclusion: This review demonstrates high incidence and prevalence levels for patellofemoral pain. Within the context of this, and poor long term prognosis and high disability levels, PFP should be an urgent research priority

Activation and Deactivation of a Robust Immobilized Cp*Ir-Transfer Hydrogenation Catalyst: A Multielement in Situ X-ray Absorption Spectroscopy Study

A highly robust immobilized [Cp*IrCl2]2 precatalyst on Wang resin for transfer hydrogenation, which can be recycled up to 30 times, was studied using a novel combination of X-ray absorption spectroscopy (XAS) at Ir L3-edge, Cl K-edge, and K K-edge. These culminate in in situ XAS experiments that link structural changes of the Ir complex with its catalytic activity and its deactivation. Mercury poisoning and “hot filtration” experiments ruled out leached Ir as the active catalyst. Spectroscopic evidence indicates the exchange of one chloride ligand with an alkoxide to generate the active precatalyst. The exchange of the second chloride ligand, however, leads to a potassium alkoxide–iridate species as the deactivated form of this immobilized catalyst. These findings could be widely applicable to the many homogeneous transfer hydrogenation catalysts with Cp*IrCl substructure

MicroRNA control of drug-resistance in haematological malignancies

miRNAs have been shown to play a role in fundamental cellular processes. They are also involved in drug-resistance mechanisms, which hamper the treatment of many types of cancer, including haematological malignancies. This study sought to uncover mechanisms of miRNA-induced drug-resistance in two haematological malignancies: diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). To this end, profiling of DLBCL and MM-derived cell lines was carried out to identify miRNAs whose levels were altered relative to their respective controls. The expression levels of these miRNAs were then modulated in the cell lines to examine the effect upon cell survival. The miRNA profiling data of the DLBCL cell lines compared to their control “normal” B-cell lines, was then combined with the results of previously performed “translational profiling” in which levels of mRNA translation are compared. Translational profiling identified upregulation of certain DNA damage repair (including BRCA2) and anti-apoptotic (including Bcl-2) proteins in the DLBCL cell lines. Importantly, the miRNA profiling data identified downregulation of miR-34a and miR-146 in the DLBCL cell lines, which are reported to target Bcl-2 and BRCA2, respectively. In GCB-DLBCL patient samples low miR-34a expression correlated with poor prognosis. In MM, the miRNA profile of an acquired multidrug-resistant cell line (8226/R5) was compared with the profile of its parental sensitive cell line and the miR-200 family was identified as upregulated in the resistant line. Overexpression of miR-200b, miR-200c or miR-429 in the parental cell line increased resistance to the proteasome inhibitor bortezomib. The increased resistance was due to direct targeting of the pro-apoptotic protein, Noxa, by the miR-200bc/429 family. Acquired bortezomib-resistant cell lines, which were only resistant to proteasome inhibitors, were then generated. miR-200b was again upregulated in these new cell lines, suggesting that increased expression of the miR-200bc/429 family is a possible mechanism for acquired bortezomib-resistance in MM

The RNA-binding protein PTBP1 is necessary for B cell selection in germinal centers.

Antibody affinity maturation occurs in germinal centers (GCs), where B cells cycle between the light zone (LZ) and the dark zone. In the LZ, GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from helper T cells, which promotes their rapid proliferation. Here we found that the RNA-binding protein PTBP1 was needed for the progression of GC B cells through late S phase of the cell cycle and for affinity maturation. PTBP1 was required for proper expression of the c-MYC-dependent gene program induced in GC B cells receiving T cell help and directly regulated the alternative splicing and abundance of transcripts that are increased during positive selection to promote proliferation