Changes in the enzymatic activity of protein arginine methyltransferase (PRMT) 5 have been associated with cancer; however, the protein's role in acute myeloid leukemia (AML) has not been fully evaluated. Here, we show that increased PRMT5 activity enhanced AML growth in vitro and in vivo while PRMT5 downregulation reduced it. In AML cells, PRMT5 interacted with Sp1 in a transcription repressor complex and silenced miR-29b preferentially via dimethylation of histone 4 arginine residue H4R3. As Sp1 is also a bona fide target of miR-29b, the miR silencing resulted in increased Sp1. This event in turn led to transcription activation of FLT3, a gene that encodes a receptor tyrosine kinase. Inhibition of PRMT5 via sh/siRNA or a first-in-class small-molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved. Collectively, our data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a 'yin-yang' functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5-miR-29b-FLT3 network should be further explored as a novel therapeutic target for AML.

Introduction Many commonly prescribed medications have inadvertent anticholinergic effects. People with Dementia (PwD) are more vulnerable to these effects and at risk of adverse outcomes, the risk being higher with a greater degree of anticholinergic exposure. We investigated prescribing patterns and Anticholinergic burden (ACB) in a cohort of community-dwelling older adults with dementia and aimed to explore the effect of ACB on cognition, mood, and quality of life(QoL). Method The medication and demographic information for 87 (39 female) community-dwelling PwD were obtained from Electronic Care Summaries. We used the German Anticholinergic Burden Scale (GABS) to measure ACB. Additionally, we investigated associations between ACB and cognitive (ADAS-Cog), functional (BADL) and QoL (DemQoL) assessments. Results 28.7% of participants had a clinically significant score (ACB> 2). The most commonly prescribed medications with ACB were Lansoprazole(18.3%), Mirtazapine(12.6%) and Codeine(12.6%). ACB was higher in males and negatively correlated with age, r(87)=-.21,p=.03. There was no association between ACB and cognition, QoL, functional independence, and neuropsychiatric symptoms. Over six months, PLWD with no ACB had a greater negative change in neuropsychiatric symptoms[t(18)=2.27,p=.04] and functional independence[t(23)=-3.8,p=.001], indicating greater dependence and worsening neuropsychiatric symptoms. Conclusion A third of PLWD in the community had clinically significant ACB. No ACB was associated with worsening neuropsychiatric symptoms and functional dependence over a six-month period. Community prescribers should consider regular medication reviews with PLWD and carers to ensure medications are prescribed safely and appropriately.