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The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis.
Tran, Tiffany M; Philipp, Julia; Bassi, Jaspal Singh; Nibber, Neha; Draper, Jolene M; Lin, Tasha L; Palanichamy, Jayanth Kumar; Jaiswal, Amit Kumar; Silva, Oscar; Paing, May; King, Jennifer; Katzman, Sol; Sanford, Jeremy R; Rao, Dinesh S.
Afiliación
  • Tran TM; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
  • Philipp J; Molecular, Cellular, and Integrative Physiology Interdepartmental Ph.D. Program, UCLA, Los Angeles, CA, 90095, USA.
  • Bassi JS; Department of Molecular, Cellular and Developmental Biology, UCSC, Santa Cruz, CA, 95064, USA.
  • Nibber N; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
  • Draper JM; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
  • Lin TL; Department of Molecular, Cellular and Developmental Biology, UCSC, Santa Cruz, CA, 95064, USA.
  • Palanichamy JK; Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA, 90095, USA.
  • Jaiswal AK; Molecular Biology Interdepartmental Doctoral Program, UCLA, Los Angeles, CA, 90095, USA.
  • Silva O; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
  • Paing M; Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.
  • King J; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
  • Katzman S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Sanford JR; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
  • Rao DS; Division of Rheumatology, Department of Medicine, UCLA, Los Angeles, CA, 90095, USA.
Leukemia ; 36(1): 68-79, 2022 01.
Article en En | MEDLINE | ID: mdl-34321607
Despite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes. Here, we find that the RNA-binding protein IGF2BP3, which is overexpressed in MLL-translocated leukemia, strongly amplifies MLL-Af4-mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4-driven leukemia and greatly attenuates disease, with a minimal impact on baseline hematopoiesis. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. At the molecular level, IGF2BP3 regulates a complex posttranscriptional operon governing leukemia cell survival and proliferation. IGF2BP3-targeted mRNA transcripts include important MLL-Af4-induced genes, such as those in the Hoxa locus, and the Ras signaling pathway. Targeting of transcripts by IGF2BP3 regulates both steady-state mRNA levels and, unexpectedly, pre-mRNA splicing. Together, our findings show that IGF2BP3 represents an attractive therapeutic target in this disease, providing important insights into mechanisms of posttranscriptional regulation in leukemia.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Leucemia Experimental / Regulación Leucémica de la Expresión Génica / Proteínas de Fusión Oncogénica / N-Metiltransferasa de Histona-Lisina / Proteínas de Unión al ARN / Proteínas de Unión al ADN / Proteína de la Leucemia Mieloide-Linfoide / Carcinogénesis Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Nucleares / Leucemia Experimental / Regulación Leucémica de la Expresión Génica / Proteínas de Fusión Oncogénica / N-Metiltransferasa de Histona-Lisina / Proteínas de Unión al ARN / Proteínas de Unión al ADN / Proteína de la Leucemia Mieloide-Linfoide / Carcinogénesis Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Leukemia Asunto de la revista: HEMATOLOGIA / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido