YBX1 mediates translation of oncogenic transcripts to control cell competition in AML

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.

Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms

“…To further assess the functional importance of KDM4C in JAK2-mutated cells, we used a CRISPR–Cas9-mediated gene-editing and negative-selection strategy (Fig. 4A , as described before [ 11 ]). Genetic deletion was confirmed by Western blotting, and PCR.…”

“…Genetic editing by CRISPR/Cas9 was performed as previously described [ 11 , 12 ] unless otherwise stated. Guide RNAs were designed using the Broad GPP tool (Doench, Nat Biotechnology 2014).…”

Differential co‐expression network analysis elucidated genes associated with sensitivity to farnesyltransferase inhibitor and prognosis of acute myeloid leukemia

“…81 The recent study showed that YBX1 is a particular dependency and therapeutic target in AML, required for oncogenic protein production. 82 The malignancy of various cancers has been associated with the presence of tumor-infiltrating immune cells. Determining the status of the immune response in individual patients at each stage of the disease is critical for deciding subsequent clinical diagnosis and treatment.…”

tRNA derived small RNAs—Small players with big roles

“…A few studies reported that tRFs were able to regulate transcript stability and translation by interacting with RNA Binding Proteins (RBP). YBX1 is an RBP that enhances the translation of several oncogenic transcripts by binding to and stabilizing them ( Perner et al, 2022 ). The majority of YBX1-binding sites in these transcripts were localized to 3′ UTRs and exons ( Goodarzi et al, 2015 ).…”