Browsing by MeSH term "N-Myc Proto-Oncogene Protein"
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Publication Myc is dispensable for cardiomyocyte development but rescues Mycn-deficient hearts through functional replacement and cell competition.(The Company of Biologists, 2019-02-01) Munoz Martin, Noelia; Sierra, Rocio; Schimmang, Thomas; Villa del Campo, Cristina; Torres, Miguel; Fondation Leducq; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III; Fundación La Caixa; Fundación ProCNICMyc is considered an essential transcription factor for heart development, but cardiac defects have only been studied in global Myc loss-of-function models. Here, we eliminated Myc by recombining a Myc floxed allele with the Nkx2.5Cre driver. We observed no anatomical, cellular or functional alterations in either fetuses or adult cardiac Myc-deficient mice. We re-examined Myc expression during development and found no expression in developing cardiomyocytes. In contrast, we confirmed that Mycn is essential for cardiomyocyte proliferation and cardiogenesis. Mosaic Myc overexpression in a Mycn-deficient background shows that Myc can replace Mycn function, recovering heart development. We further show that this recovery involves the elimination of Mycn-deficient cells by cell competition. Our results indicate that Myc is dispensable in cardiomyocytes both during cardiogenesis and for adult heart homeostasis, and that Mycn is exclusively responsible for cardiomyocyte proliferation during heart development. Nonetheless, our results show that Myc can functionally replace Mycn We also show that cardiomyocytes compete according to their combined Myc and Mycn levels and that cell competition eliminates flawed cardiomyocytes, suggesting its relevance as a quality control mechanism in cardiac development.Publication The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status(Nature Publishing Group, 2019-11-28) Trigg, Ricky M; Lee, Liam C; Prokoph, Nina; Jahangiri, Leila; Reynolds, C Patrick; Amos Burke, G A; Probst, Nicola A; Han, Miaojun; Matthews, Jamie D; Lim, Hong Kai; Manners, Eleanor; Martinez, Sonia; Pastor Fernandez, Joaquin; Blanco-Aparicio, Carmen; Merkel, Olaf; Garces de Los Fayos Alonso, Ines; Kodajova, Petra; Tangermann, Simone; Högler, Sandra; Luo, Ji; Kenner, Lukas; Turner, Suzanne D; Children with Cancer UK; Cancer Research UK (Reino Unido); Unión Europea. Comisión Europea. European Research Council (ERC)Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.