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­PNAS Papers on AML Tumorigenesis, Pancreatic Cancer Inhibition, Adult T-Cell Leukemia/Lymphoma

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

In a study scheduled to appear in PNAS this week, a University of North Carolina-Chapel Hill-led team explores stemness pathway contributions to tumorigenicity in aggressive forms of acute myeloid leukemia (AML) marked by MLL alterations or NUP98 andNSD1 gene rearrangements. Using RNA sequencing, chromatin immunoprecipitation-sequencing, and an epigenetic profiling assay called "cleavage under targets & release," the researchers saw signs that chromatin associations help the lysine demethylase Kdm5b suppresses stem cell-like features in AML — a process that is itself repressed by polycomb repressive complex 2 (PRC2) and PRC2's H3K27 methylase enzyme activity. These and other findings suggest that the "AML-suppressing role of Kdm5b is not dependent on its intrinsic demethylase activity but requires its scaffold and/or chromatin association functions," the authors report, arguing that such results may inform future therapeutic strategies.

German researchers describe synthetic lethal ties between RUNX1 transcription factor inhibition and higher-than-usual expression of the pro-apoptosis protein NOXA in pancreatic ductal adenocarcinoma (PDAC). With the help of a drug screen — together with RNA sequencing, ChIP-seq, ATAC-seq, CRISPR-based gene editing, and other approaches — the team found that PDAC growth could be curbed in mouse models of the disease and in patient-derived organoids using a compound that inhibits RUNX1. RUNX1 inhibition, in turn, appeared to boost NOXA-related apoptosis through epigenetic changes, including a shift in histone features found in the promoter of the NOXA-coding gene. "Our study unravels a function of the transcription factor RUNX1 in apoptosis regulation in PDAC," they write. "We show that pharmacological RUNX1 inhibition in PDAC is feasible and leads to NOXA-dependent apoptosis."

A team from China and Japan digs into the oncogenic role that the Hippo/Yap pathway plays in some virus-induced malignancies, particularly adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell cancer linked to human T-cell leukemia virus type 1 (HTLV-1) infection. With gene expression and other analyses in peripheral blood mononuclear cells from 14 individuals with or without ATL, along with follow-up cell line and mouse xenograft model experiments, the investigators saw lower-than-usual levels of the Hippo tumor suppressor pathway and enhanced YAP transcription and NF-kappa-B-related YAP activation in the HTLV-1-infected cells, in part due to the activity of a viral protein called Tax. "[W]e have shown that HTLV-1 infection dysregulates the Hippo signaling pathway and induces the activation of YAP through two mechanisms: Tax-mediated stimulation of YAP gene transcription and TAX-mediated NF-kappa-B activation of the YAP protein," they write, adding that "HTLV-1 may take advantage of these mechanisms to allow infected cells to proliferate."

Filed under

The Scan

Hormone-Based Gene Therapy to Sterilize Domestic Cat

A new paper in Nature Communication suggests that gene therapy could be a safer alternative to spaying domestic cats.

Active Lifestyle Linked to Type 2 Diabetes Prevention in People at High Genetic Risk

A study in the British Journal of Sports Medicine shows that an active lifestyle goes a long way in type 2 diabetes prevention.

Beneficial, Harmful Effects of Introgression Between Wild and Domesticated European Grapes

A paper in PNAS shows that European wild grapevines were an important resource for improving the flavor of cultivated wine grapes.

Genetic Ancestry of South America's Indigenous Mapuche Traced

Researchers in Current Biology analyzed genome-wide data from more than five dozen Mapuche individuals to better understand their genetic history.