Platelet Pathogen Reduction Technology-Should We Stay or Should We Go…?

The recent COVID-19 pandemic has significantly challenged blood transfusion services (BTS) for providing blood products and for keeping blood supplies available. The possibility that a similar pandemic event may occur again has induced researchers and transfusionists to investigate the adoption of new tools to prevent and reduce these risks. Similarly, increased donor travelling and globalization, with consequent donor deferral and donor pool reduction, have contributed to raising awareness on this topic.

Combination Therapies Targeting Apoptosis in Paediatric AML: .

Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no "standard approach" exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be targeted. Our in silico analysis of AML patients highlighted "cell death and survival" as an aberrant, potentially targetable pathway in paediatric AML patients.

Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors.

Unlabelled: Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response to DNA damage. Here, we demonstrate that depletion of SF3B1 specifically compromises homologous recombination (HR) and is epistatic with loss of BRCA1.

Multiplex Screening for Interacting Compounds in Paediatric Acute Myeloid Leukaemia.

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease.

Erythropoietin in bone homeostasis-Implications for efficacious anemia therapy.

Bone homeostasis and hematopoiesis are irrevocably linked in the hypoxic environment of the bone marrow. Erythropoietin (Epo) regulates erythropoiesis by binding to its receptor, Epor, on erythroid progenitor cells. The continuous process of bone remodeling is achieved by the finely balanced activity of osteoblasts in bone synthesis and osteoclasts in bone resorption.

A compound combination screening approach with potential to identify new treatment options for paediatric acute myeloid leukaemia.

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by genetics and morphology. The introduction of intensive chemotherapy treatments together with patient stratification and supportive therapy has resulted in a moderate improvement in patient prognosis. However, overall survival rates remain unacceptably poor, with only 65% of patients surviving longer than 5 years.

Chronic loss of STAG2 leads to altered chromatin structure contributing to de-regulated transcription in AML.

Background: The cohesin complex plays a major role in folding the human genome into 3D structural domains. Mutations in members of the cohesin complex are known early drivers of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with STAG2 the most frequently mutated complex member.

Methods: Here we use functional genomics (RNA-seq, ChIP-seq and HiChIP) to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming in a clinically relevant model of chronic STAG2 loss.

Altered splicing and cytoplasmic levels of tRNA synthetases in SF3B1-mutant myelodysplastic syndromes as a therapeutic vulnerability.

Myelodysplastic syndromes (MDS) are haematopoietic malignancies that are characterised by a heterogeneous clinical course. In recent years, sequencing efforts have uncovered recurrent somatic mutations within RNA splicing factors, including SF3B1, SRSF2, U2AF1 and ZRSR2. The most frequently mutated gene is SF3B1, mutated in 17% of MDS patients.

Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes.

Genetic lesions affecting epigenetic regulators are frequent in myelodysplastic syndromes (MDS). Polycomb proteins are key epigenetic regulators of differentiation and stemness that act as two multimeric complexes termed polycomb repressive complexes 1 and 2, PRC1 and PRC2, respectively. While components and regulators of PRC2 such as ASXL1 and EZH2 are frequently mutated in MDS and AML, little is known about the role of PRC1.

Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy.

Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment.