Loss of Function of TET2 Cooperates with Constitutively Active KIT in Murine and Human Models of Mastocytosis

Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM

Swiss Survey on current practices and opinions on clinical constellations triggering the search for PNH clones.

UNLABELLED This national survey investigated the current practice in Switzerland by collecting participants' opinions on paroxysmal nocturnal hemoglobinuria (PNH) clone assessment and clinical practice. AIM This study aimed to investigate clinical indications prompting PNH clones' assessment and physician's accessibility of a flow cytometry facility, and also to understand clinical attitudes on the follow-up (FU) of patients with PNH clones. METHODS The survey includes 16 multiple-choice questions related to PNH and targets physicians with a definite level of experience in the topic using two screener questions. Opinion on clinical management was collected using hypothetical clinical situations. Each participant had the option of being contacted to further discuss the survey results. This was an online survey, and 264 physicians were contacted through email once a week for 5 weeks from September 2020. RESULTS In total, 64 physicians (24.2%) from 23 institutions participated (81.3% hematologists and 67.2% from university hospitals). All had access to flow cytometry for PNH clone testing, with 76.6% having access within their own institution. The main reasons to assess for PNH clones were unexplained thrombosis and/or hemolysis, and/or aplastic anemia (AA). Patients in FU for PNH clones were more likely to be aplastic anemia (AA) and symptomatic PNH. In total, 61% of the participants investigated PNH clones repetitively during FU in AA/myelodysplastic syndromes patients, even when there was no PNH clone found at diagnosis, and 75% of the participants tested at least once a year during FU. Opinions related to clinical management were scattered. CONCLUSION The need to adhere to guidelines for the assessment, interpretation, and reporting of PNH clones emerges as the most important finding, as well as consensus for the management of less well-defined clinical situations. Even though there are several international guidelines, clear information addressing specific topics such as the type of anticoagulant to use and its duration, as well as the indication for treatment with complement inhibitors in some borderline situations are needed. The analysis and the discussion of this survey provide the basis for understanding the unmet needs of PNH clone assessment and clinical practice in Switzerland

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Astrocytes play an important role in nervous system homeostasis. In particular, they contribute to the regulation of local energy metabolism and to oxidative stress defence. In previous experiments, we showed that long-term treatment with interleukin 1alpha (IL-1alpha) or tumor necrosis factor-alpha (TNFalpha) alone increases glucose utilization in primary culture of mouse astrocytes. In our study, we report that a combination of IL-1beta and TNFalpha exerts a synergistic effect on glucose utilization and markedly modifies the metabolic phenotype of astrocytes. Thus, IL-1beta+TNFalpha treated astrocytes show a marked decrease in glycogen levels, a slight but not significant decrease in lactate release as well as a massive increase in both the pentose phosphate pathway and TCA cycle activities. Glutamate-stimulated glucose utilization and lactate release, a typical feature of astrocyte energy metabolism, are altered after pretreatment with IL-1beta+TNFalpha. As far as mechanisms for oxidative stress defence are concerned, we observed that treatment with IL-1beta+TNFalpha decreases cellular glutathione content and increases glutathione release into the extracellular space while stimulating superoxide anion and nitric oxide production as well as H(2)O(2) release. Interestingly, stimulation of glucose utilization by IL-1beta+TNFalpha is not affected by the antioxidant N-acetyl-L-cysteine, suggesting that cellular stress does not account for this effect. Finally, the effects of cytokines on glucose utilization appear to involve multiple signaling cascades including the phosphoinositide 3-kinase and mitogen-activated protein kinases. Taken together these results establish that a proinflammatory environment such as observed in several neuropathological conditions including Alzheimer's disease, markedly modifies the metabolic phenotype of astrocytes.LND

Une dyspnée pas comme les autres, ou quand on parle du loup.. [Unusual cause for a dyspnea.].

We report the case of a patient presenting with late onset systemic lupus erythematosus presenting as a haemolytic anemia and pleuritis. We describe the clinical features, diagnosis, prognosis and treatment of the disease with special focus on haematological and pulmonary involvement