Abstract-Apoptosis has been causally linked to the pathogenesis of myocardial infarction and heart failure in rodent models. This death process is mediated by two central pathways, an extrinsic pathway involving cell surface receptors and an intrinsic pathway using mitochondria and the endoplasmic reticulum. Each of these pathways has been implicated in myocardial pathology. In this review, we summarize recent advances in the understanding of the intrinsic pathway and how it relates to cardiac myocyte death and heart disease. Key Words: apoptosis Ⅲ necrosis Ⅲ cell death Ⅲ mitochondria Ⅲ Bcl-2 Ⅲ caspase Ⅲ death-inducing signaling complex Ⅲ apoptosome Ⅲ ischemia Ⅲ heart failure O ver the past decade, interest in cell death has intensified among scientists in multiple areas of biology and medicine. This fascination has been driven by the discovery that apoptosis is mediated by an ancient program that is hard-wired into all metazoan cells. Renewed attention in the cardiovascular field has been fueled by the notion that cell death is often an active process that, in principle, can be inhibited in various disease states.

The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL-derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with the IGH locus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-offunction mutation that promotes constitutive dimerization and cytokine independent growth. A mutually exclusive subset harbors activating mutations in JAK2. In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL. Expression of WT CRLF2 with mutant JAK2 also promotes cytokine independent growth that, unlike CRLF2 Phe232Cys or ligand-induced signaling by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, cells dependent on CRLF2 signaling are sensitive to small molecule inhibitors of either JAKs or protein kinase C family kinases. Together, these findings implicate CRLF2 as an important factor in B-ALL with diagnostic, prognostic, and therapeutic implications.uring the past decade, studies using oligonucleotide arrays and high-throughput sequencing have identified several genetic and transcriptional aberrations in B-cell acute lymphoblastic leukemia (B-ALL) (1), leading to three conceptual advances. First, genes involved in normal B-cell development (e.g., PAX5, IKZF1) are frequently mutated in B-ALL (1-3). Second, B-ALL is highly heterogeneous and can exist as multiple, genetically distinct clones within the same individual (1, 4). Third, B-ALL transcriptional profiles cluster based on characteristic chromosomal rearrangements, hereafter defined as rearrangements of TEL, MLL, TCF3, and BCR/ABL (5-8).However, one third of B-ALL cases lack characteristic rearrangements (9). Transcriptional profiles from a subset of these leukemias cluster with profiles from BCR/ABL-expressing B-ALL (3, 5), suggesting that the former harbor cryptic alterations in tyrosine kinase signaling. Supporting this notion, mutations in JAKs were recently identified in a small percentage of pediatric B-ALL and approximately 20% of ALL in children with Down syndrome (10-14).Upon ligand binding to a type I cytokine receptor, JAKs phosphorylate substrates including STATs, which in turn affect the transcription of progrowth and antiapoptotic factors (15). JAK enzymatic activity requires interaction with a cytokine receptor, which is believed to se...

Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.