Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signaling and characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using MxCre;Ptpn11 mice, which model human JMML, we show that RAS pathway activation affects apoptosis signaling through cell type-dependent regulation of BCL-2 family members. Apoptosis resistance observed in monocytes and granulocytes was mediated by overexpression of the anti-apoptotic and down-regulation of the pro-apoptotic members of the BCL-2 family.

CD21 B cells reveal a unique glycosylation pattern with hypersialylation and hyperfucosylation.

Background: The posttranslational modification of cellular macromolecules by glycosylation is considered to contribute to disease pathogenesis in autoimmune and inflammatory conditions. In a subgroup of patients with common variable immunodeficiency (CVID), the occurrence of such complications is associated with an expansion of naïve-like CD21 B cells during a chronic type 1 immune activation. The glycosylation pattern of B cells in CVID patients has not been addressed to date.

Improved Quantification of Circulating Tumor DNA in Translocation-Associated Myxoid Liposarcoma by Simultaneous Detection of Breakpoints and Single Nucleotide Variants.

Background: Myxoid liposarcomas (MLS) can exhibit a disseminated metastatic pattern, necessitating extensive diagnostics during follow-up. With no tumor markers available, early diagnosis of recurrences and tumor monitoring is difficult. The detection of circulating tumor DNA (ctDNA; liquid biopsy) in MLS with the characteristic translocations t(12;16) and t(12;22) can provide an additional diagnostic.

KDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells.

KDM5C is commonly mutated in clear cell renal cell carcinomas (ccRCC) in men but rarely in women. Introducing KDM5C mutation into two male and two female KDM5C wild-type ccRCC cell lines caused different phenotypes and non-overlapping transcriptional consequences, indicative of context-dependent functions of KDM5C. We identify that loss of the Y chromosome, harbouring the KDM5C homologue KDM5D, occurs in most male KDM5C mutant ccRCCs.

Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity.

Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development.