The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis
| Autor: | Oscar Silva, J. King, May Paing, Julia Philipp, Dinesh S. Rao, Tasha L. Lin, Tiffany M. Tran, Jaspal Bassi, Sol Katzman, Jeremy R. Sanford, Amit Kumar Jaiswal, Jolene M. Draper, Neha Nibber, Jayanth Kumar Palanichamy |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
0301 basic medicine
Cancer Research Oncogene Proteins Fusion Operon Carcinogenesis RNA-binding protein Apoptosis Inbred C57BL Mice 0302 clinical medicine hemic and lymphatic diseases Leukaemia 2.1 Biological and endogenous factors Aetiology Cancer Mice Knockout Oncogene Proteins Leukemic Leukemia Cancer stem cells Gene Expression Regulation Leukemic RNA-Binding Proteins Nuclear Proteins Hematology Cell biology DNA-Binding Proteins Haematopoiesis Oncology 030220 oncology & carcinogenesis RNA splicing Female Myeloid-Lymphoid Leukemia Protein Knockout Clinical Sciences Oncology and Carcinogenesis Immunology Biology Article 03 medical and health sciences Experimental Rare Diseases medicine Genetics Animals Fusion Gene neoplasms Cell Proliferation Messenger RNA Leukemia Experimental Oncogenes Histone-Lysine N-Methyltransferase medicine.disease Mice Inbred C57BL 030104 developmental biology Ras Signaling Pathway Gene Expression Regulation |
| Zdroj: | Leukemia, vol 36, iss 1 Leukemia |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|