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The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.

Objectives A systematic review was conducted in high-income country settings to analyse: (i) spina bifida neonatal and IMRs over time, and (ii) clinical and socio-demographic factors associated with mortality in the first year after birth in infants affected by spina bifida. Data sources PubMed, Embase, Ovid, Web of Science, CINAHL, Scopus and the Cochrane Library were searched from 1st January, 1990 to 31st August, 2020 to review evidence. Study selection Population-based studies that provided data for spina bifida infant mortality and case fatality according to clinical and socio-demographical characteristics were included. Studies were excluded if they were conducted solely in tertiary centres. Spina bifida occulta or syndromal spina bifida were excluded where possible. Data extraction and synthesis Independent reviewers extracted data and assessed their quality using MOOSE guideline. Pooled mortality estimates were calculated using random-effects (+/- fixed effects) models meta-analyses. Heterogeneity between studies was assessed using the Cochrane Q test and I2 statistics. Meta-regression was performed to examine the impact of year of birth cohort on spina bifida infant mortality. Results Twenty studies met the full inclusion criteria with a total study population of over 30 million liveborn infants and approximately 12,000 spina bifida-affected infants. Significant declines in spina bifida associated infant and neonatal mortality rates (e.g. 4.76% decrease in IMR per 100, 000 live births per year) and case fatality (e.g. 2.70% decrease in infant case fatality per year) were consistently observed over time. Preterm birth (RR 4.45; 2.30–8.60) and low birthweight (RR 4.77; 2.67–8.55) are the strongest risk factors associated with increased spina bifida infant case fatality. Significance Significant declines in spina bifida associated infant/neonatal mortality and case fatality were consistently observed, advances in treatment and mandatory folic acid food fortification both likely play an important role. Particular attention is warranted from clinicians caring for preterm and low birthweight babies affected by spina bifida.