Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis.

Protein synthesis is frequently deregulated during tumorigenesis. However, the precise contexts of selective translational control and the regulators of such mechanisms in cancer is poorly understood. Here, we uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in myeloid leukemia. Elevated CNOT3 expression correlates with unfavorable outcomes in patients with acute myeloid leukemia (AML). CNOT3 depletion induces differentiation and apoptosis and delayed leukemogenesis. Transcriptomic and proteomic profiling uncovers c-MYC as a critical downstream target which is translationally regulated by CNOT3. Global analysis of mRNA features demonstrates that CNOT3 selectively influences expression of target genes in a codon usage dependent manner. Furthermore, CNOT3 associates with the protein network largely consisting of ribosomal proteins and translation elongation factors in leukemia cells. Overall, our work elicits the direct requirement for translation efficiency in tumorigenesis and propose targeting the post-transcriptional circuitry via CNOT3 as a therapeutic vulnerability in AML.

RNA modifications in hematological malignancies.

RNA modifications play an important role in various cancers including blood cancers by controlling gene expression programs critical for survival, proliferation and differentiation of cancer cells. While hundreds of RNA modifications have been identified, many have not been functionally characterized. With development of enabling technologies to identify and map RNA modifications, tremendous advancement has been made in our understanding of the biological functions of these molecular markers in diverse cellular contexts. In the last 5 years, N6-methyladenosine (m6A), the most prevalent internal mRNA modification, has been extensively implicated in many facets of leukemogenesis. Other types of RNA modifications are also involved in the regulation of cell fate decisions and tumorigenesis. Here, we summarize existing knowledge and recent discoveries regarding the role of RNA modifications in leukemia. We choose to highlight cutting-edge techniques to characterize and profile RNA modifications while discussing critical functions of key modifiers and regulatory mechanisms in the pathogenesis of hematological malignancies and touch on therapeutic strategies targeting RNA modifications. These important advancements in the field will continue to foster a strong foundation for the development of innovative treatments for hematological malignancies.