Aberrant MNX1 expression associated with t(7;12)(q36;p13) pediatric acute myeloid leukemia induces the disease through altering histone methylation

Certain subtypes of acute myeloid leukemia (AML) in children have inferior outcome, such as AML with translocation t(7;12)(q36;p13) leading to an MNX1::ETV6 fusion along with high expression of MNX1. We have identified the transforming event in this AML and possible ways of treatment. Retroviral expression of MNX1 was able to induce AML in mice, with similar gene expression and pathway enrichment to t(7;12) AML patient data. Importantly, this leukemia was only induced in immune incompetent mice using fetal but not adult hematopoietic stem and progenitor cells. The restriction in transforming capacity to cells from fetal liver is in alignment with t(7;12)(q36;p13) AML being mostly seen in infants. Expression of MNX1 led to increased histone 3 lysine 4 mono-, di- and trimethylation, reduction in H3K27me3, accompanied with changes in genome-wide chromatin accessibility and genome expression, likely mediated through MNX1 interaction with the methionine cycle and methyltransferases. MNX1 expression increased DNA damage, depletion of the Lin-/Sca1+/c-Kit+ population and skewing toward the myeloid lineage. These effects, together with leukemia development, were prevented by pre-treatment with the S-adenosylmethionine analog Sinefungin. In conclusion, we have shown the importance of MNX1 in development of AML with t(7;12), supporting a rationale for targeting MNX1 and downstream pathways

BDNF increases the number of axotomized rat retinal ganglion cells expressing GAP-43, L1, and TAG-1 mRNA--a supportive role for nitric oxide?

The death of neurons and the limited ability to activate growth-associated genes prevent the restoration of lesioned fiber tracts in the adult mammalian CNS. Here, we characterized the effects of the survival-promoting neurotrophin brain-derived neurotrophic factor (BDNF) on mRNA expression of GAP-43, L1, TAG-1, and SC-1 in axotomized and regenerating rat retinal ganglion cells (RGCs). BDNF led to de novo upregulation of TAG-1 mRNA in axotomized RGCs and to a threefold increase in the number of GAP-43 and L1 mRNA-expressing RGCs. SC-1 expression remained unchanged. However, BDNF did not improve long-distance axon regeneration into a peripheral nerve graft. Surprisingly, potentiating BDNF-mediated neuroprotection by simultaneous administration of a spin trap or a NOS inhibitor counteracted the BDNF-induced growth-associated gene expression. This led us to hypothesize that the BDNF effects on GAP-43, L1, and TAG-1 mRNA expression are mediated by a NO-dependent mechanism. In summary, our data support the idea that survival and axon regeneration of lesioned CNS neurons can be regulated independently

Short-term fasting accompanying chemotherapy as a supportive therapy in gynecological cancer: protocol for a multicenter randomized controlled clinical trial

Background/objectives: A few preliminary studies have documented the safety and feasibility of repeated short-term fasting in patients undergoing chemotherapy. However, there is a lack of data from larger randomized trials on the effects of short-term fasting on quality of life, reduction of side effects during chemotherapy, and a possible reduction of tumor progression. Moreover, no data is available on the effectiveness of fasting approaches compared to so-called healthy diets. We aim to investigate whether the potentially beneficial effects of short-term fasting can be confirmed in a larger randomized trial and can compare favorably to a plant-based wholefood diet. Methods: This is a multicenter, randomized, controlled, two-armed interventional study with a parallel group assignment. One hundred fifty patients, including 120 breast cancer patients and 30 patients with ovarian cancer, are to be randomized to one of two nutritional interventions accompanying chemotherapy: (1) repeated short-term fasting with a maximum energy supply of 350–400 kcal on fasting days or (2) repeated short-term normocaloric plant-based diet with restriction of refined carbohydrates. The primary outcome is disease-related quality of life, as assessed by the functional assessment of the chronic illness therapy measurement system. Secondary outcomes include changes in the Hospital Anxiety and Depression Score and as well as frequency and severity of chemotherapy-induced side effects based on the Common Terminology Criteria of Adverse Events. Explorative analysis in a subpopulation will compare histological complete remissions in patients with neoadjuvant treatments. Discussion/planned outcomes: Preclinical data and a small number of clinical studies suggest that repeated short-term fasting may reduce the side effects of chemotherapy, enhance quality of life, and eventually slow down tumor progression. Experimental research suggests that the effects of fasting may partly be caused by the restriction of animal protein and refined carbohydrates. This study is the first confirmatory, randomized controlled, clinical study, comparing the effects of short-term fasting to a short-term, plant-based, low-sugar diet during chemotherapy on quality of life and histological tumor remission. Trial registration. ClinicalTrials.gov NCT03162289. Registered on 22 May 201

Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma

<p>Cholangiocarcinoma (CC) is a rare malignancy of the extrahepatic or intrahepatic biliary tract with an outstanding poor prognosis. Non-surgical therapeutic regimens result in minimally improved survival of CC patients. Global genomic analyses identified a few recurrently mutated genes, some of them in genes involved in epigenetic patterning. In a previous study, we demonstrated global DNA methylation changes in CC, indicating major contribution of epigenetic alterations to cholangiocarcinogenesis. Here, we aimed at the identification and characterization of CC-related, differentially methylated regions (DMRs) in potential microRNA promoters and of genes targeted by identified microRNAs. Twenty-seven hypermethylated and 13 hypomethylated potential promoter regions of microRNAs, known to be associated with cancer-related pathways like Wnt, ErbB, and PI3K-Akt signaling, were identified. Selected DMRs were confirmed in 2 independent patient cohorts. Inverse correlation between promoter methylation and expression suggested miR-129-2 and members of the miR-200 family (miR-200a, miR-200b, and miR-429) as novel tumor suppressors and oncomiRs, respectively, in CC. Tumor suppressor genes <i>deleted in liver cancer 1</i> (<i>DLC1</i>), <i>F-box/WD-repeat-containing protein 7</i> (<i>FBXW7</i>), and <i>cadherin-6</i> (<i>CDH6</i>) were identified as presumed targets in CC. Tissue microarrays of a representative and well-characterized cohort of biliary tract cancers (n=212) displayed stepwise downregulation of CDH6 and association with poor patient outcome. Ectopic expression of <i>CDH6</i> on the other hand, delayed growth in the CC cell lines EGI-1 and TFK-1, together suggesting a tumor suppressive function of <i>CDH6</i>. Our work represents a valuable repository for the study of epigenetically altered miRNAs in cholangiocarcinogenesis and novel putative, CC-related tumor suppressive miRNAs and oncomiRs.</p