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PNAS Papers on Australian Mammal Museum Genomics, CD47 Blockade for Breast Cancer, More

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

Investigators at the University of Melbourne and elsewhere dig into museum samples going as far back as 184 years in an effort to understand features found in now-extinct rodents in Australia, which has been home to a wide range of historical mammalian extinctions. With the help of targeted capture, targeted exon sequencing, or exome sequencing, the team sequenced 87 individuals spanning eight extinct and 48 extant hydromyine rodent species, using the data to put together a phylogenetic tree going back some 5.2 million years. "We find no evidence for reduced genetic diversity in extinct species just prior to or during decline, indicating that their extinction was extremely rapid," the authors report. "This suggests that populations of extinct Australian rodents were large prior to European colonization, and that genetic diversity does not necessarily protect species from catastrophic extinction."

A team from the US and Israel look at a potential role for CD47 blockade therapy to reduce resistance to the anti-HER2 drug trastuzumab in HER2-positive forms of breast cancer. With a series of cell line experiments and in vivo tumor growth assays in mouse models, the researchers found that combining trastuzumab with a CD47-targeting humanized monoclonal antibody called Hu5F9-G4 could curb the growth of HER2-positive breast cancer cells that are otherwise capable of tolerating antibody-dependent cellular toxicity induced by the anti-HER2 treatment. "Collectively, our findings present a promising therapeutic approach for the treatment of HER2-positive breast cancer patients whose tumors are either trastuzumab-sensitive or -resistant, as long as the epitope recognized by the therapeutic anti-HER2 antibody remains intact," they write, noting that "other human-engineered IgG1 tumor-targeting antibodies might yield similar therapeutic results when combined with CD47 blockade (and/or other macrophage checkpoint inhibitors), offering a useful adjunct to anti-tumor antibody treatment."

Finally, researchers from China and the US explore the function of a H3K79 methyltransferase enzyme called DOT1L that is known to be dysregulated in mixed-lineage leukemia (MLLr). Using a 4sUDRB sequencing strategy for following polymerase II (Pol II) enzyme elongation in erythroleukemic cells with lower-than-usual levels of DOT1L or other members of the same complex, the team saw signs that DOT1L does not seem to make major contributions to regulating transcriptional elongation, despite physically localizing near Pol II in the cell. Rather, results from these and other experiments suggested that a complex containing DOT1L regulates transcriptional initiation. "Collectively," the authors conclude, "the various recruitment mechanisms for modified DOT1L complexes could contribute, through effects on initiation and elongation, to maintenance of the expression of key target genes of [MLL fusion proteins] in MLLr leukemias."

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