RNA deadenylation, the process of shortening of the 3' poly(A) tail of an RNA molecule, is one of the key steps of post-transcriptional regulation of gene expression in eukaryotic cells. PAN2/3 and ...CCR4-NOT (CNOT) are the two dominant RNA deadenylation complexes, which play central roles in mediating mRNA decay and translation. While degradation is the final fate of virtually all RNAs in their life cycles, selection of RNA targets as well as control of the rate and timing of RNA decay, in coordination with other molecular pathways, including translation, can be modulated in certain contexts. Such regulation influences cell growth, proliferation, and differentiation at the cellular level; and contributes to establish polarity and regulate signaling at the tissue level. Dysregulation of deadenylation processes have also been implicated in human diseases ranging from cardiac diseases and neurodevelopmental disorders to cancers. In this review, we will discuss mechanisms of gene expression control mediated by the RNA deadenylation complexes and highlight relevant evidence supporting the emerging roles of RNA deadenylation and its regulatory proteins during development and in diseases. A systemic understanding of these mechanisms will be a critical foundation for development of effective strategies to therapeutically target them.
N
-methyladenosine (m
A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m
A ...modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m
A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m
A coupled with ribosome profiling reveals that m
A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.
In the rapidly evolving landscape of medical research, the emergence of RNA-based therapeutics is paradigm shifting. It is mainly driven by the molecular adaptability and capacity to provide ...precision in targeting. The Covid-19 pandemic crisis underscored the effectiveness of the mRNA therapeutic development platform and brought it to the forefront of RNA-based interventions. These RNA-based therapeutic approaches can reshape gene expression, manipulate cellular functions, and correct aberrant molecular processes underlying various diseases. The new technologies hold the potential to engineer and deliver tailored therapeutic agents to tackle genetic disorders, cancers, infectious diseases in a highly personalized and precisely tuned manner. The review discusses most recent advancements in the field of mRNA therapeutics for cancer treatment, with a focus on the features of the most utilized RNA-based therapeutic interventions, current pre-clinical and clinical developments and the remaining challenges in delivery strategies, effectiveness, and safety considerations.
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Vu and colleagues offer an insightful overview of RNA-based therapy, a recently emerged as an exciting therapeutic approach. The review describes the rational design of synthetic mRNA and strategies to deliver mRNAs, and an extensive discussion of current developments as well as safety and regulatory consideration for clinical applications of the technologies.
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, N
6
-methyladenosine (m
6
A), 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.
The cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA ...editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors. Additionally, we discover a significant increase in RNA binding activity of MSI2 in leukemic stem cells compared with normal hematopoietic stem and progenitor cells, resulting in selective regulation of MSI2's oncogenic targets. This provides a basis for MSI2 increased dependency in leukemia cells compared to normal cells. Moreover, our study provides a way to measure RBP function in rare cells and suggests that RBPs can achieve differential binding activity during cell state transition independent of gene expression.
Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and ...lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multiprotein repressor complex that includes DPF2. As part of the feedback loop, PRMT4 expression is repressed posttranscriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells in vitro and their decreased proliferation in vivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.
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•PRMT4 blocks myeloid differentiation of human hematopoietic stem/progenitor cells•PRMT4 is downregulated by miR-223 during normal myeloid differentiation•PRMT4 represses miR-223 expression by assembling a methyl-RUNX1-dependent complex•Knockdown of PRMT4 reduces the leukemia cell burden in an AML mouse model
Zhao, Nimer, and colleagues now find that the arginine methyltransferase PRMT4 inhibits myeloid differentiation of human stem/progenitor cells. Inhibition occurs through recruitment of a methylation-dependent repressor complex that negatively regulates miR-223 expression. The authors show that PRMT4 is highly expressed in acute myeloid leukemia patient samples and that depletion of PRMT4 reduces leukemia burden in a mouse model. This work provides insights into the role of PRMT4 in normal and malignant hematopoiesis and identifies PRMT4 as an attractive therapeutic target in cancer.
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.
One of the biggest challenges in treating acute myeloid leukemia (AML) is relapse of aggressive disease after treatment. In this issue of Cancer Cell, Boyd et al. characterize a molecularly distinct ...population of chemotherapy-induced transient leukemic regenerating cells (LRCs), which can be exploited to prevent AML recurrence.
One of the biggest challenges in treating acute myeloid leukemia (AML) is relapse of aggressive disease after treatment. In this issue of Cancer Cell, Boyd et al. characterize a molecularly distinct population of chemotherapy-induced transient leukemic regenerating cells (LRCs), which can be exploited to prevent AML recurrence.
Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term ...repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.
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