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Research Roundup: December 14, 2018

By Broad Communications

Mapping cancer resistance workarounds, probing promoters in autism, profiling microbes' metabolism in IBD, and more.

Welcome to the December 14, 2018 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Examining the cells of CLL

Transcriptional dysregulation has been observed in cancer cells from patients with chronic lymphocytic leukemia (CLL), but a comprehensive understanding of factors driving this aberrant cell state has been lacking. Now a team led by the Cancer Program's Christopher Ott, Jennifer Brown, and James Bradner has mapped the transcriptional regulatory circuitry of the disease, comparing cells from patient samples to healthy B cells. The researchers identified an essential transcription factor — PAX5 —that dominates the cancer cells’ circuitry, and a potential therapeutic route to shut down this network. Learn more in Cancer Cell.

Broken protein, broken rhythm

Atrial fibrillation (Afib), a condition that causes a rapid, irregular heartbeat, is quite rare among people under the age of 65, suggesting a strong but so far elusive genetic component. In this week's JAMA, the Cardiovascular Disease Initiative's Seung Hoan Choi, associate member Patrick Ellinor, and colleagues in the NHLBI's TOPMed Consortium linked mutations that break titin, a protein associated with several kinds of cardiomyopathy, to one's risk of developing early-onset Afib. Interestingly, their data show that the younger a person is diagnosed with Afib, the more likely they are to have a mutation in titin. Read more in a Broad news story.

A BETter roadmap of resistance

To study how cancer cells become resistant to chromatin-remodeling drugs, a team led by institute member Kimberly Stegmaier and Amanda Balboni Iniguez in the Cancer Program used functional genomics screens, -omic profiling of drug-resistant cells, and drug combination screens to uncover mechanisms of resistance to BET inhibitors in neuroblastoma. Reporting in Cancer Cell, they found that resistant cells undergo PI3K pathway activation via enhancer remodeling and transcriptional reprogramming. The work suggests that PI3K and BET inhibitors could be an effective combination for preventing resistance, and offers a roadmap for identifying resistance to epigenetically targeted drugs in other cancers.  

A new threat to cancer cells

PARP inhibitors, which limit the ability of tumor cells to repair damage and replicate, have shown promise as therapies for certain forms of ovarian and breast cancer. In a new study led by Cancer Program associate member Jean Zhao and Ursula Matulonis at Dana-Farber Cancer Institute (DFCI), researchers discovered that the tumor-fighting effects of these drugs are more robust than previously understood. In mice with BRCA-mutated ovarian cancer, the team showed that PARP inhibitors triggered a local and systemic antitumor immune response, and that this response was improved when the inhibitor was combined with an immunotherapy drug. Read more in Cell Reports, and a Dana-Farber press release.

Promoter permutations promote autism

Researchers have found numerous connections between autism spectrum disorder (ASD) and gene mutations, but have yet to forge similar links with the genome’s noncoding DNA. Using more than 1,900 families' whole genome data and two new approaches (category-wide association study [CWAS] analysis and de novo risk scoring), associate member Michael Talkowski, members of the Stanley Center for Psychiatric Research and the Program in Medical and Population Genetics, and colleagues nationwide with the Autism Sequencing Consortium and the Simons Foundation Autism Research Initiative have identified a strong signal connecting spontaneous variations in gene promoters with ASD. Their study, reported in Science as part of a package from the National Institute of Mental Health's PsychENCODE consortium, marks the first genome-wide examination of de novo noncoding mutations' roles in ASD. Learn more in press releases from Carnegie Mellon University, UCSF, and the Simons Foundation.

Profiling the microbe-metabolite connection in IBD

Inflammatory bowel diseases (IBDs) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic conditions of the gastrointestinal tract caused by changes in the interactions between gut microbes and the intestinal immune system. However, researchers do not fully understand how microbes alter metabolites in the gut to cause IBD. To address that, a team led by Eric Franzosa, Alexandra Sirota-Madi, Hera Vlamakis, Curtis Huttenhower and institute member Ramnik Xavier in the Infectious Disease and Microbiome Program performed metabolomic and metagenomic profiling of faecal samples collected from cohorts of CD, UC, and non-IBD control patients. Reporting in Nature Microbiology, the team provides detailed findings of IBD-related perturbations caused at the microbiome and metabolome interface. This new understanding will help identify both diagnostic and therapeutic targets in the future.

Resistance in metastatic breast cancer

For most breast cancer patients, drugs that target the estrogen receptor are the mainstay of treatment. If the cancer becomes resistant, it’s often due to genetic mutations in this receptor — but not always. In Nature Genetics, a team led by Utthara Nayar, Ofir Cohen, and Cancer Program associate member Nikhil Wagle reports mutations in the human epidermal growth factor receptor 2 (HER2) that can also induce this drug resistance. The researchers demonstrated in cell lines that the resistance could be reversed with a combination therapy, using the HER2 kinase inhibitor neratinib. Read more in a press release from DFCI.

Blood cell (im)balance

As we age, the balance of new blood cells produced in our bodies begins to shift toward myeloid cells over lymphoid cells. This imbalance can sometimes lead to impaired immunity, even leukemia. A new study published in Cell Reports, led by researchers in the labs of Klarman Cell Observatory director and core institute member Aviv Regev and David Baltimore at CalTech, describes how the stem cells that produce these new blood cells respond differently to foreign bacteria the older we get. Using single-cell RNA-sequencing, the researchers discovered a new subclass of blood stem cells, ones that are biased toward myeloid cells and that increase in number as we age. When the researchers exposed these cells to bacteria, their numbers increased, leading the team to speculate that exposure to bacterial infections over a lifetime may cause these biased cells to multiply.

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