15 research outputs found

    Gα13 and Rho Mediate Endosomal Trafficking of CXCR4 into Rab11 +

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    Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

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    Epigenetic regulators play critical roles in normal hematopoiesis, and the activity of these enzymes is frequently altered in hematopoietic cancers. The major type II protein arginine methyltransferase PRMT5 catalyzes the formation of symmetric dimethyl arginine and has been implicated in various cellular processes, including pluripotency and tumorigenesis. Here, we generated Prmt5 conditional KO mice to evaluate the contribution of PRMT5 to adult hematopoiesis. Loss of PRMT5 triggered an initial but transient expansion of hematopoietic stem cells (HSCs); however, Prmt5 deletion resulted in a concurrent loss of hematopoietic progenitor cells (HPCs), leading to fatal BM aplasia. PRMT5-specific effects on hematopoiesis were cell intrinsic and depended on PRMT5 methyltransferase activity. We found that PRMT5-deficient hematopoietic stem and progenitor cells exhibited severely impaired cytokine signaling as well as upregulation of p53 and expression of its downstream targets. Together, our results demonstrate that PRMT5 plays distinct roles in the behavior of HSCs compared with HPCs and is essential for the maintenance of adult hematopoietic cells

    RELIEF OF PROFOUND FEEDBACK INHIBITION OF MITOGENIC SIGNALING BY RAF INHIBITORS ATTENUATES THEIR ACTIVITY IN BRAFV600E MELANOMAS

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    BRAFV600E drives tumors by dysregulating ERK signaling. Here we show that, in these tumors, high levels of ERK-dependent negative feedback potently suppress liganddependent mitogenic signaling and Ras function. BRAFV600E activation is Rasindependent and signals as a RAF-inhibitor sensitive monomer. RAF inhibitors potently inhibit RAF monomers and ERK signaling, causing relief of ERK-dependent feedback, reactivation of ligand-dependent signal transduction, increased Ras-GTP and generation of RAF inhibitor-resistant RAF dimers. This results in a rebound in ERK activity and culminates in a new steady state, wherein ERK signaling is elevated compared to its initial nadir after RAF inhibition. In this state, ERK signaling is RAF inhibitor resistant, and MEK inhibitor sensitive, and combined inhibition results in enhancement of ERKpathway inhibition and antitumor activity

    CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis

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    Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML. [Display omitted] •Conditional knockout of Carm1 has little effect on normal hematopoiesis•Loss of Carm1 abrogates the initiation and maintenance of AML in mouse models•CARM1 knockdown impairs cell-cycle progression and induces apoptosis in AML cells•A potent and selective CARM1 inhibitor impairs AML cell proliferation Greenblatt et al. show that loss of the protein arginine methyltransfersase CARM1 minimally impacts normal hematopoiesis but strongly impairs leukemogenesis by regulating cell-cycle progression, myeloid differentiation, and apoptosis. Targeting CARM1 reduces AML growth in primary patient samples and mouse models
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