YBX1 mediates translation of oncogenic transcripts to control cell competition in AML
Research output: Contribution to journal › Journal article › Research › peer-review
Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.
Original language | English |
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Journal | Leukemia |
Volume | 36 |
Issue number | 2 |
Pages (from-to) | 426-437 |
Number of pages | 12 |
ISSN | 0887-6924 |
DOIs | |
Publication status | Published - Feb 2022 |
Externally published | Yes |
Bibliographical note
© 2021. The Author(s).
- Animals, Apoptosis, Biomarkers, Tumor/genetics, Cell Competition, Cell Proliferation, Humans, Janus Kinase 2/genetics, Leukemia, Myeloid, Acute/genetics, Mice, Mutation, Prognosis, Proto-Oncogene Proteins c-myc/genetics, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Y-Box-Binding Protein 1/genetics
Research areas
ID: 303116628