The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins

Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers

Quantitative, multiplexed, targeted proteomics for ascertaining variant specific SARS-CoV-2 antibody response

Determining the protection an individual has to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VoCs) is crucial for future immune surveillance, vaccine development, and understanding of the changing immune response. We devised an informative assay to current ELISA-based serology using multiplexed, baited, targeted proteomics for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. Serum from individuals collected after infection or first- and second-dose vaccination demonstrates this approach and shows concordance with existing serology and neutralization. Our assays show altered responses of both immunoglobulins and complement to the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.1) VoCs and a reduced response to Omicron (B1.1.1529). We were able to identify individuals who had prior infection, and observed that C1q is closely associated with IgG1 (r > 0.82) and may better reflect neutralization to VoCs. Analyzing additional immunoproteins beyond immunoglobulin (Ig) G, provides important information about our understanding of the response to infection and vaccination

Lead Toxicity: What is it and How is it Happening?

EPIDEMIOLOGY Lead poisoning accounts for 0.6% of the global burden of disease. In Pennsylvania in 2010, 148,751 children under 72 months of age were tested for blood lead levels. Of those children, 19,176 had blood lead levels greater than 5 μg/dl. A lower socioeconomic status increases the chances for lead exposure. Lead toxicity is an under-appreciated problem that is entirely preventable

LETTERS Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras

The cascade comprising Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) is a therapeutic target in human cancers with deregulated Ras signalling, which includes tumours that have inactivated the Nf1 tumour suppressor 1,2 . Nf1 encodes neurofibromin, a GTPaseactivating protein that terminates Ras signalling by stimulating hydrolysis of Ras-GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed because of outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4 and Mapk14, which encodes p38a. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance. Aberrant Ras signalling contributes to the pathogenesis of myeloid malignancies and can result from acquired RAS mutations or from alternative genetic mechanisms that include FLT3 internal tandem duplications, the BCR-ABL fusion, PTPN11 mutations and NF1 inactivation (reviewed in ref. 3). Children with neurofibromatosis type 1 (NF1) have a 200-to 500-fold excess incidence of juvenile myelomonocytic leukaemia, an aggressive MPD characterized by leukocytosis, splenomegaly and tissue infiltration (reviewed in ref. 4). The bone marrows of affected patients frequently show loss of the normal parental NF1 allele and elevated ERK activity flox/flox pups to identify genes and pathways that might cooperate with Nf1 inactivation to induce progression of MPD to AML 3 . These mice developed acute leukaemia sooner and at a higher rate than control Mx1-Cre-negative littermates that retain normal Nf1 functio

The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity

Studies have shown that the immune system can recognize self-antigens under conditions (eg, cell injury) in which the self-tissue might elaborate immune-activating endogenous danger signals. Uric acid (UA) is an endogenous danger signal recently identified to be released from dying cells. Prior work has shown that UA activates immune effectors of both the innate and adaptive immune system, including neutrophils and cytotoxic T-cell immunity. However, it was unclear whether UA could enhance antibody immunity, which was examined in this study. When added to dying tumor cells or with whole protein antigen, UA increased IgG1-based humoral immunity. Further, UA blocked growth of tumor in subsequent tumor challenge experiments, which depended on CD4, but not CD8, T cells. Sera derived from UA-treated animals enhanced tumor growth, suggesting it had little role in the antitumor response. UA did not signal for T-cell expansion or altered tumor-infiltrating leukocyte populations. Consistent with the lack of T-cell expansion, when applied to dendritic cells, UA suppressed T-cell growth factors but up-regulated B cell–activating cytokines. Understanding the nature of endogenous danger signals released from dying cells may aid in a better understanding of mechanisms of immune recognition of self