Weekly Top Scientific Research Review (27/3/2017 – 31/3/2017)

A new week is coming. Some interesting materials have been waiting for you. Let’s surfing together!

1. LACTB is a tumour suppressor that modulates lipid metabolism and cell state.

Weekly Top Scientific Research Review (27/3/2017 – 31/3/2017)Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. Zuzana Keckesova at Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, USA and his colleagues hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here they show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.

Read more, please click http://www.nature.com/nature/journal/vaop/ncurrent/full/nature21408.html

2. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1.

Chronic myeloid leukaemia (CML) is driven by the activity of the BCR–ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here, Andrew A. Wylie at Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, USA and his colleagues characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.

Read more, please click http://www.nature.com/nature/journal/vaop/ncurrent/full/nature21702.html

3. Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions.

Identification of effective combination therapies is critical to address the emergence of drug-resistant cancers, but direct screening of all possible drug combinations is infeasible. Here, Kyuho Han at Stanford University in Stanford, California, USA and his colleagues introduce a CRISPR-based double knockout (CDKO) system that improves the efficiency of combinatorial genetic screening using an effective strategy for cloning and sequencing paired single guide RNA (sgRNA) libraries and a robust statistical scoring method for calculating genetic interactions (GIs) from CRISPR-deleted gene pairs. The team applied CDKO to generate a large-scale human GI map, comprising 490,000 double-sgRNAs directed against 21,321 pairs of drug targets in K562 leukemia cells and identified synthetic lethal drug target pairs for which corresponding drugs exhibit synergistic killing. These included the BCL2L1 and MCL1 combination, which was also effective in imatinib-resistant cells. They further validated this system by identifying known and previously unidentified GIs between modifiers of ricin toxicity. This work provides an effective strategy to screen synergistic drug combinations in high-throughput and a CRISPR-based tool to dissect functional GI networks.

Read more, please click http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3834.html

4. GuideScan software for improved single and paired CRISPR guide RNA design.

Alexendar R Perez at Memorial Sloan Kettering Cancer Center in New York, USA and his colleagues present GuideScan software for the design of CRISPR guide RNA libraries that can be used to edit coding and noncoding genomic regions. GuideScan produces high-density sets of guide RNAs (gRNAs) for single- and paired-gRNA genome-wide screens. They also show that the trie data structure of GuideScan enables the design of gRNAs that are more specific than those designed by existing tools.

Read more, please click http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3804.html

5. Highly efficient RNA-guided base editing in mouse embryos.

Base editors (BEs) composed of a cytidine deaminase fused to CRISPR-Cas9 convert cytidine to uridine, leading to single-base-pair substitutions in eukaryotic cells. Kyoungmi Kim at Institute for Basic Science in Seoul, Republic of Korea and his colleagues delivered BE mRNA or ribonucleoproteins targeting the Dmd or Tyr gene via electroporation or microinjection into mouse zygotes. F0 mice showed nonsense mutations with an efficiency of 44-57% and allelic frequencies of up to 100%, demonstrating an efficient method to generate mice with targeted point mutations.

Read more, please click http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3816.html

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