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PNAS Papers on Childhood Periodic Fever, Mutant TERT-BRAF Interactions, AML Microenvironment

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.

In a study slated to appear in the PNAS this week, researchers from the National Human Genome Research Institute and other centers consider genetic contributors to a pediatric periodic fever syndrome known as "periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis" (PFAPA) syndrome. The team searched for common variants contributing to PFAPA susceptibility in more than 200 individuals from European-American or Turkish cohorts affected by PFAPA, focusing on half a dozen SNPs previously linked to other conditions such as recurrent aphthous stomatitis and Behçet's disease. "In light of the phenotypic similarities among Behçet's disease, recurrent aphthous stomatitis, and PFAPA, we hypothesized that these diseases may also have genotypic overlap," the author say, noting that their analyses unearthed shared risk variants in genes such as IL12A, IL10, STAT4, and CCR1-CCR3, along with potential human leukocyte antigen ties to phenotype in individuals with conditions on the Behçet's disease spectrum.

A Johns Hopkins University School of Medicine-led team takes a look at TERT promoter mutations influencing BRAF and MEK inhibitor responses in cancers containing the BRAF V600E mutation for another upcoming PNAS paper. When they compared responses to the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in 19 thyroid cancer, melanoma, and colon cancer cell lines, the researchers saw pronounced proapoptotic effects in cancer cells containing the BRAF V600E mutation in combination with TERT promoter changes — an effect that was muted in cell lines with the BRAF V600E mutation alone. That pattern appeared to carry over to in vivo xenograft tumors grown in mice for the preclinical study, they report, prompting them to suggest that "TERT promoter mutation governs BRAF-mutant cancers' apoptotic, and hence therapeutic responses to BRAF/MEK inhibitors, providing potential value in assisting patient selection for treatment and in predicting treatment outcomes."

Researchers from the Oregon Health and Science University and elsewhere report on reversible T immune cell suppression patterns identified in bone marrow samples surrounding acute myeloid leukemia (AML). Reasoning that the AML microenvironment may influence the risk of relapse after initial success in treating the blood cancer, the team used functional and proliferation assays, CyTOF-based immunophenotyping, and other approaches to profile T cell patterns in bone marrow samples from 49 individuals with AML and from eight healthy donors. Along with T cell suppression, which appeared to be released with immune checkpoint blockade treatments, the analysis highlighted apparent ties between T cell infiltration in AML patients at the time of diagnosis and better-than-usual survival outcomes. "Our data demonstrate that AML establishes an immune suppressive environment in the bone marrow, in part through T cell checkpoint function," the authors write.