The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis.

Autor: Tran TM; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.; Molecular, Cellular, and Integrative Physiology Interdepartmental Ph.D. Program, UCLA, Los Angeles, CA, 90095, USA., Philipp J; Department of Molecular, Cellular and Developmental Biology, UCSC, Santa Cruz, CA, 95064, USA., Bassi JS; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA., Nibber N; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA., Draper JM; Department of Molecular, Cellular and Developmental Biology, UCSC, Santa Cruz, CA, 95064, USA., Lin TL; Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA, 90095, USA.; Molecular Biology Interdepartmental Doctoral Program, UCLA, Los Angeles, CA, 90095, USA., Palanichamy JK; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.; Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India., Jaiswal AK; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA., Silva O; Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA., Paing M; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA., King J; Division of Rheumatology, Department of Medicine, UCLA, Los Angeles, CA, 90095, USA., Katzman S; UCSC Genomics Institute, Santa Cruz, CA, 95064, USA., Sanford JR; Department of Molecular, Cellular and Developmental Biology, UCSC, Santa Cruz, CA, 95064, USA., Rao DS; Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA. DRao@mednet.ucla.edu.; Molecular, Cellular, and Integrative Physiology Interdepartmental Ph.D. Program, UCLA, Los Angeles, CA, 90095, USA. DRao@mednet.ucla.edu.; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, 90095, USA. DRao@mednet.ucla.edu.; Broad Stem Cell Research Center, UCLA, Los Angeles, CA, 90095, USA. DRao@mednet.ucla.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Jan; Vol. 36 (1), pp. 68-79. Date of Electronic Publication: 2021 Jul 29.
DOI: 10.1038/s41375-021-01346-7
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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