A novel flow cytometry-based assay to measure compromised B cell receptor signaling as a prognostic factor in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. In the past years, new therapeutic approaches (e.g., ibrutinib or venetoclax) have been established and greatly improved treatment of CLL. However, complete control or cure of the disease have not been reached so far. Thus, reliable prognostic markers are an imperative for treatment decisions. Recent studies have revealed an essential role for B cell receptor (BCR) signaling in the pathogenesis, prognosis, and therapy of CLL. A heterogeneous response to receptor stimulation with anti-IgM treatment culminating in different calcium flux capabilities has been demonstrated by several authors. However, the methods employed have not reached clinical application. Here, we report on a flow cytometry-based assay to evaluate calcium flux capabilities in CLL and demonstrate that compromised BCR signaling with diminished calcium flux is associated with a significantly better clinical outcome and progression free survival. In summary, our data strongly support the role of compromised BCR signaling as an important prognostic marker in CLL and establish a novel diagnostic tool for its assessment in clinical settings.

NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.

Diet-induced obesity accelerates the onset of terminal phenotypes in α-synuclein transgenic mice.

Parkinson's disease (PD) and diabetes belong to the most common neurodegenerative and metabolic syndromes, respectively. Epidemiological links between these two frequent disorders are controversial. The neuropathological hallmarks of PD are protein aggregates composed of amyloid-like fibrillar and serine-129 phosphorylated (pS129) α-synuclein (AS). To study if diet-induced obesity could be an environmental risk factor for PD-related α-synucleinopathy, transgenic (TG) mice, expressing the human mutant A30P AS in brain neurons, were subjected after weaning to a lifelong high fat diet (HFD). The TG mice became obese and glucose-intolerant, as did the wild-type controls. Upon aging, HFD significantly accelerated the onset of the lethal locomotor phenotype. Coinciding with the premature movement phenotype and death, HFD accelerated the age of onset of brainstem α-synucleinopathy as detected by immunostaining with antibodies against pathology-associated pS129. Amyloid-like neuropathology was confirmed by thioflavin S staining. Accelerated onset of neurodegeneration was indicated by Gallyas silver-positive neuronal dystrophy as well as astrogliosis. Phosphorylation of the activation sites of the pro-survival signaling intermediate Akt was reduced in younger TG mice after HFD. Thus, diet-induced obesity may be an environmental risk factor for the development of α-synucleinopathies. The molecular and cellular mechanisms remain to be further elucidated. Life-long high fat diet (HFD) induces obesity and glucose intolerance in a transgenic mouse model for α-synucleinopathy and thereby leads to decreased life span as well as accelerated age of onset of the terminal phenotype. This is accompanied by increased neuroinflammation and premature α-synuclein pathology in the brainstems of the HFD-fed mice.