Alex C.H. Liu

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

Mutant isocitrate dehydrogenase 1 (IDH1) and IDH2 block the differentiation of acute myeloid leukemia (AML) cells through production of R-2-hydroxyglutarate (R-2-HG). IDH inhibitors can induce differentiation of AML cells by lowering R-2-HG but have limited clinical efficacy as single agents. Here, we performed a genome-wide CRISPR knockout screen in an Idh1-mutated hematopoietic progenitor cell line to identify genes that increased the differentiation response to ivosidenib, an IDH1 inhibitor. The screen identified C-type lectin member 5a (Clec5a), which encodes a spleen tyrosine kinase (SYK)-coupled surface receptor, as one of the top hits. Knockout of Clec5a and Syk rendered cells more sensitive to ivosidenib-induced differentiation through a reduction in STAT5-dependent expression of stemness-related genes, including genes in the homeobox (HOX) family. Importantly, direct inhibition of STAT5 activity was sufficient to increase the differentiation response to IDH inhibitors in primary human IDH1- and IDH2-mutated AML cells, including those harboring mutations in receptor tyrosine kinase (RTK) and MAPK genes that have been linked to drug resistance. In patient-derived xenograft models of IDH1-mutated AML, combination treatment with ivosidenib and the STAT5 inhibitor pimozide was superior to each agent alone in inducing differentiation in leukemic cells without compromising normal hematopoiesis. These findings demonstrate that STAT5 is a critical mediator of resistance to IDH inhibitors and provide the rationale for combining STAT5 and IDH inhibitors in the treatment of IDH-mutated AML. SIGNIFICANCE: A CRISPR knockout screen identifies a mechanism of resistance to IDH inhibitors in AML involving activated STAT5 signaling, suggesting a potential strategy to improve the clinical efficacy of IDH inhibitors.

BACKGROUND: Understanding both cost and quality across institutions is a critical first step to illuminating the value of care purchased by Medicare. Under contract with the Centers for Medicare and Medicaid Services, we developed a method for profiling hospitals by 30-day episode-of-care costs (payments for Medicare beneficiaries) for acute myocardial infarction (AMI). METHODS: We developed a hierarchical generalized linear regression model to calculate hospital risk-standardized payment (RSP) for a 30-day episode for AMI. Using 2008 Medicare claims, we identified hospitalizations for patients 65 years of age or older with a discharge diagnosis of ICD-9 codes 410.xx. We defined an AMI episode as the date of admission plus 30 days. To reflect clinical care, we omitted or averaged payment adjustments for geographic factors and policy initiatives. We risk-adjusted for clinical variables identified in the 12 months preceding and including the AMI hospitalization. Using combined 2008-2009 data, we assessed measure reliability using an intraclass correlation coefficient and calculated the final RSP. RESULTS: The final model included 30 variables and resulted in predictive ratios (average predicted payment/average total payment) close to 1. The intraclass correlation coefficient score was 0.79. Across 2382 hospitals with ≥ 25 hospitalizations, the unadjusted mean payment was $20,324 ranging from $11,089 to $41,897. The mean RSP was $21,125 ranging from $13,909 to $28,979. CONCLUSIONS: This study introduces a claims-based measure of RSP for an AMI 30-day episode of care. The RSP varies among hospitals, with a 2-fold range in payments. When combined with quality measures, this payment measure will help profile high-value care.