Abstract
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.
Highlights
Cold-shock proteins (CSPs) are a family of multifunctional DNA/ RNA binding proteins that contain a highly conserved nucleic acid binding domain called the cold shock domain
Compared to healthy donors (HD), patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) showed increased expression during disease progression with the highest scores documented in the AML specimens (Fig. 1E)
Cold shock protein YBX1 has been identified as a pan-cancer dependency in publicly available CRISPR-Cas9-screens and several studies in different tumor entities
Summary
Cold-shock proteins (CSPs) are a family of multifunctional DNA/ RNA binding proteins that contain a highly conserved nucleic acid binding domain called the cold shock domain. YBX1 is a pleiotropic DNA and RNA binding protein that modulates translation, RNA-stability, mRNA splicing, transcription or cell signaling depending on cell type and genetic background [1,2,3,4,5,6,7,8,9,10]. YBX1 binds and stabilizes oncogenic RNAs in the context of hypoxia [2] and directly mediates translation of HIF1a transcripts [1, 15]. Genetic inactivation of YBX1 led to a significant increase in mis-splicing of MAPK/ERK pathway members and to eradication of otherwise persistent MPN cells [16]. YBX1 was not primarily required for proliferation or survival of JAK2-mutated cells
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