A Northwestern University-led team takes a look at potential strategies for targeting forms of leukemia with translocations involving the MLL gene. Based on RNA sequencing analyses, small hairpin RNA screening, and other experiments on leukemic cell lines, the researchers suggest that there may be a therapeutic benefit to stabilizing wild-type MLL via the UBE20 ubiquitin ligase enzyme and the interleukin-1 pathway in leukemias with MLL rearrangements. "[W]e found that wild type MLL protein is much less abundant than the MLL chimeras in MLL leukemia cells," they say. "Therefore, we reasoned that the stabilization of the wild type copy of the MLL protein could displace MLL chimeras from chromatin and, therefore, evade the oncogenic addiction of these cells to MLL chimeras."
Overlapping regions of the HIV-1 genome that code for genes with distinct functional roles may offer some fitness advantages to the virus, according to work by a University of California, San Francisco, team. The investigators aligned sequences from thousands of HIV isolates from patients to explore the mutational constraints in the overlapping tat and rev genes. For example, their results suggest that while the tat and rev genes share overlapping sequences, residues relevant to the function of one gene or the other did not. "Our comprehensive analysis reveals the extraordinary manner in which HIV minimizes the constraint of overlapping genes and repurposes that constraint to its own advantage," they write.
Researchers from the Broad Institute, Massachusetts Institute of Technology, and elsewhere introduce a strategy that combines single-cell RNA sequencing method with CRISPR/Cas9-based multi-locus genetic screening. The team used the approach, dubbed Perturb-seq, to characterize 200,000 cells from human cell lines and in stimulated or unstimulated bone marrow-derived dendritic cell lines in which transcription factors or other gene were targeted with CRISPR/Cas9 methods. "Perturb-seq accurately identifies individual gene targets, gene signatures, and cell states affected by individual perturbations and their genetic interactions," the authors say.