Multiple myeloma forecasting, nerve growth guidance, modeling Alzheimer's mechanisms, and more
Research Roundup: June 12, 2020
Welcome to the June 12, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Predicting disease progression in myeloma
Smoldering multiple myeloma is a condition that often precedes full-blown multiple myeloma (MM). To better understand and predict the risk of disease progression, a team led by Mark Bustoros, Romanos Sklavenitis-Pistofidis, Salomon Manier (University of Lille), institute member Gad Getz, and associate member Irene Ghobiral in the Cancer Program searched patient samples for genomic alterations that underlie advancement to MM. They found variations capable of distinguishing patients at high risk, including alterations in the mitogen-activated protein kinase and DNA repair pathways, as well as Myc. Check out more in the Journal of Clinical Oncology and a news release from Dana-Farber Cancer Institute.
To study disease biology in the East Asian population, a team including postdoctoral scholar Kazuyoshi Ishigaki in the Program in Medical and Population Genetics, institute member Soumya Raychaudhuri, Johji Inazawa (Tokyo Medical and Dental University), Toshimasa Yamauchi and Takashi Kadowaki (University of Tokyo), and Michiaki Kubo Yoichiro Kamatani (RIKEN Center for Integrative Medical Sciences) tapped into the BioBank Japan Project and conducted a genome-wide association study with 212,453 Japanese individuals across 42 diseases. Reporting in Nature Genetics, the researchers detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci, including two East Asian-specific missense variants associated with coronary artery disease and lung cancer. Read more in GenomeWeb.
Follow the light
Neurons have an amazing ability to grow and build connections over long distances, but to date it has not been possible to direct axon growth in a controlled fashion. Writing in Developmental Cell, James Harris and institute member Paola Arlotta in the Stanley Center for Psychiatric Research and colleagues report the development of an optogenetics-based system that allows them to guide axons to grow and build connections along desired paths. They showed in a zebrafish model that they could direct axon growth over long distances, and overcome genetic guidance defects to create functional connections. Learn more in a story from the Harvard Department of Stem Cell and Regenerative Biology.
Closer, mechanistic view of Alzheimer’s
Most patients with Alzheimer’s disease (AD) develop a pathological condition called cerebral amyloid angiopathy (CAA), which impairs blood-brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest genetic risk factor for CAA. However, the underlying molecular and cellular mechanisms are unknown. Reporting in Nature Medicine, senior associate member Li-Huei Tsai at Broad’s Proteomics Platform and colleagues developed an induced pluripotent stem cell-based three-dimensional model and reconstructed the human BBB in vitro. Their findings highlight APOE and dysregulation of calcineurin–nuclear factor of activated T cells-signaling as potential targets in APOE4-mediated CAA and AD.
Non-coding candidate genes for glioblastoma
Graduate student Sharadha Sakthikumar, Kerstin Lindblad-Toh, scientific director of vertebrate genome biology and also a professor at Uppsala University in Sweden, and their colleagues applied whole-genome sequencing to glioblastoma (GBM) samples to identify non-coding mutations with regulatory potential, focusing on evolutionarily constrained regions of the genome. They report in Genome Biology a significant enrichment of non-coding constraint mutations in the neighborhood of 78 genes that have previously been implicated in GBM. The team also identified 1,776 other genes enriched for non-coding constraint mutations with likely regulatory potential, providing additional candidate GBM genes. The mutations in the top four genes, DLX5, DLX6, FOXA1, and ISL1, are distributed over promoters, UTRs, and multiple transcription factor binding sites. The results suggest that non-coding constraint mutations could play an essential role in GBM.