Enigmatic Ladies of the Rings: How Cohesin Dysfunction Affects Myeloid Neoplasms Insurgence

The genes of the cohesin complex exert different functions, ranging from the adhesion of sister chromatids during the cell cycle, DNA repair, gene expression and chromatin architecture remodeling. In recent years, the improvement of DNA sequencing technologies allows the identification of cohesin mutations in different tumors such as acute myeloid leukemia (AML), acute megakaryoblastic leukemia (AMKL), and myelodysplastic syndromes (MDS). However, the role of cohesin dysfunction in cancer insurgence remains elusive. In this regard, cells harboring cohesin mutations do not show any increase in aneuploidy that might explain their oncogenic activity, nor cohesin mutations are sufficient to induce myeloid neoplasms as they have to co-occur with other causative mutations such as NPM1, FLT3-ITD, and DNMT3A. Several works, also using animal models for cohesin haploinsufficiency, correlate cohesin activity with dysregulated expression of genes involved in myeloid development and differentiation. These evidences support the involvement of cohesin mutations in myeloid neoplasms

Severe steatohepatitis in a patient with a rare neutral lipid storage disorder due to ABDH5 mutation

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ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established

ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established.BackgroundInhibition of the renin-angiotensin system (RAS) prevents development of chronic allograft dysfunction in experimental animals. Whether this therapeutic approach is effective even if started when signs of allograft nephropathy are already manifested has not been investigated.MethodsTo address this issue, we studied the effect of a late treatment with the angiotensin-convertine enzyme (ACE) inhibitor trandolapril in the Fisher 344 to Lewis rat kidney transplant model. Seven months after transplant a renal biopsy was done for graft histology examination. Thereafter rats received either no treatment (allograft-none) or trandolapril until sacrifice at month 13.ResultsAll animals were alive at the end of the study with the exception of a rat in the untreated group that died of renal insufficiency at day 292. Despite the fact that the grafts had already signs of structural injury and function impairment at the time treatment was stated, trandolapril completely restored renal function to baseline pretransplant values. Trandolapril also halted the progression of glomerular damage and suppressed intragraft T-lymphocyte infiltration and reduced the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1). However, trandolapril had no direct effect on T cell function, since in vivo treatment did not modify recipient T-cell alloreactivity against donor antigens.ConclusionThese findings provide the basis for a novel treatment intervention with RAS blockade that, together with pharmacologic inhibition of the immune response, could interrupt progression of chronic allograft dysfunction and injury

ADA2 regulates inflammation and hematopoietic stem cell emergence via the A_2bR pathway in zebrafish

Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the adenosine deaminase 2 (ADA2) gene. Clinical manifestations of DADA2 include vasculopathy and immuno-hematological abnormalities, culminating in bone marrow failure. A major gap exists in our knowledge of the regulatory functions of ADA2 during inflammation and hematopoiesis, mainly due to the absence of an ADA2 orthologue in rodents. Exploring these mechanisms is essential for understanding disease pathology and developing new treatments. Zebrafish possess two ADA2 orthologues, cecr1a and cecr1b, with the latter showing functional conservation with human ADA2. We establish a cecr1b-loss-of-function zebrafish model that recapitulates the immuno-hematological and vascular manifestations observed in humans. Loss of Cecr1b disrupts hematopoietic stem cell specification, resulting in defective hematopoiesis. This defect is caused by induced inflammation in the vascular endothelium. Blocking inflammation, pharmacological modulation of the A2r pathway, or the administration of the recombinant human ADA2 corrects these defects, providing insights into the mechanistic link between ADA2 deficiency, inflammation and immuno-hematological abnormalities. Our findings open up potential therapeutic avenues for DADA2 patients

Low Nephron Number Induced by Maternal Protein Restriction Is Prevented by Nicotinamide Riboside Supplementation Depending on Sirtuin 3 Activation

A reduced nephron number at birth, due to critical gestational conditions, including maternal malnutrition, is associated with the risk of developing hypertension and chronic kidney disease in adulthood. No interventions are currently available to augment nephron number. We have recently shown that sirtuin 3 (SIRT3) has an important role in dictating proper nephron endowment. The present study explored whether SIRT3 stimulation, by means of supplementation with nicotinamide riboside (NR), a precursor of the SIRT3 co-substrate nicotinamide adenine dinucleotide (NAD+), was able to improve nephron number in a murine model of a low protein (LP) diet. Our findings show that reduced nephron number in newborn mice (day 1) born to mothers fed a LP diet was associated with impaired renal SIRT3 expression, which was restored through supplementation with NR. Glomerular podocyte density, as well as the rarefaction of renal capillaries, also improved through NR administration. In mechanistic terms, the restoration of SIRT3 expression through NR was mediated by the induction of proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α). Moreover, NR restored SIRT3 activity, as shown by the reduction of the acetylation of optic atrophy 1 (OPA1) and superoxide dismutase 2 (SOD2), which resulted in improved mitochondrial morphology and protection against oxidative damage in mice born to mothers fed the LP diet. Our results provide evidence that it is feasible to prevent nephron mass shortage at birth through SIRT3 boosting during nephrogenesis, thus providing a therapeutic option to possibly limit the long-term sequelae of reduced nephron number in adulthood

Uncropped blot images included in the manuscript’s main figures and supplemental figures.

All images were acquired on Odyssey FC Imaging System (LiCor, Lincoln, Nebraska, USA). In each blot, α-tubulin was used as sample loading control. Molecular weights (MW) are reported for each gel and expressed in kilo Dalton (kDa). X indicates lanes not included in the final figures. Abbreviations: WT, wild type mice; Sirt3-/-, Sirt3 knockout mice; ADR, adriamycin; VEGFA, vascular endothelial growth factor A; Angpt2, angiopoietin 2; SOD2AcK68, SOD2 acetylated at lysine 68; L-SIRT3, long SIRT3 isoform; S-SIRT3, short SIRT3 isoform (mitochondria). (PDF)</p

ADR treatment significantly downregulates renal SIRT3 expression.

Representative Western Blot and quantification of SIRT3 protein expression in WT mice treated with saline or ADR (n = 4 mice per group). Data represent mean ± SEM and were analysed with Student’s t-test. °°°P (TIF)</p

<i>Sirt3</i> deficiency and/or ADR treatment do not affect VEGFR1 expression.

Representative immunohistochemical images of VEGFR1 and quantification in WT and Sirt3-/- mice receiving saline or ADR (n = 4 mice, WT+saline and Sirt3-/-+ADR; n = 3 mice, WT+ADR and Sirt3-/-+saline). Data represent mean ± SEM and were analyzed by one-way ANOVA followed by Tukey’s multiple comparisons test. Scale bar, 20 μm. (TIF)</p