Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Wang, Eric; Lu, Sydney X.; Pastore, Alessandro; Chen, Xufeng; Imig, Jochen; Lee, Stanley Chun-Wei; Hockemeyer, Kathryn; Ghebrechristos, Yohana; Yoshimi, Akihide; Inoue, Daichi; Ki, Michelle; Cho, Hanna; Bitner, Lillian; Kloetgen, Andreas; Lin, Kuan-Ting; Uehara, Taisuke; Owa, Takashi; Tibes, Raoul; Krainer, Adrian R.; Abdel‐Wahab, Omar; Aifantis, Iannis

doi:10.1016/j.ccell.2019.01.010

Cited by 237 publications

(272 citation statements)

References 65 publications

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“…Deregulated RNA binding proteins and ribosome biogenesis can be drivers of cancer pathogenesis. 60,61 Furthermore, the GSEA analysis revealed enrichment of MYC targets in RELAPSE patients. MYC is frequently overexpressed in AML as well as other leukemic malignancies, and seems to be a crucial transcriptional factor during hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Aasebø

Berven

Bartaula-Brevik

et al. 2019

Preprint

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word count: 213 Number of figures and tables: 5 Number of references: 84 Key Points  V-ATPases and RNA processing proteins are downregulated and upregulated, respectively, in relapse patients  Relapse patients show higher activity of CSK2 and CDKs when compared to relapse-free patients AbstractAcute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly.Although complete remission (CR) is achieved for majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has therefore become of major clinical interest in AML.We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a 5-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells.This suggests that therapy against the upregulated kinases also could target the factors inducing their upregulation rather than their activity. In conclusion, our study presents markers that could help predict AML relapse and direct therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Aasebø

Berven

Bartaula-Brevik

et al. 2019

Preprint

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“…Upregulated genes in RNA splicing categories encode core spliceosomal proteins 60 , including RBM39, Snrnp200, Hnrnpn, Srsf3 and Srsf4. Upregulation of these factors has been previously linked to an increased rate of proliferation [61][62][63] . Similarly, the most strongly upregulated genes associated with DNA binding, chromatin and other significant transcriptional regulation terms include many regulators of proliferation (Hmgb2, Top2a, Mcm7, Pcna) and of neuron differentiation (Insm1, Dlx2, Tead1, Tshz1, Tcf12) [64][65][66] .…”

Section: Fmrp Loss Impacts Neuronal Homeostasismentioning

confidence: 99%

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Donnard

Shu

Garber

2020

Preprint

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Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative. We applied single cell RNA sequencing to profile a FXS mouse model. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.

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“…Among UHMSFs, CAPERα, also called RBM39, has the highest structural similarity with U2AF 65 and is the subject of a particular attention due to its role in cancer‐related splicing events and in tumor progression . The regulation of specific splicing events by CAPERα , which may be altered in acute myeloid leukemia, constitutes a putative therapeutic route . In a previous work, we illustrated the possibility that multiple CAPERα molecules bind SF3b155 in a cooperative manner .…”

Section: Introductionmentioning

confidence: 98%

U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition

et al. 2019

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The essential splicing factor U2AF65 is known to help anchoring U2 snRNP at the branch site. Its C‐terminal UHM domain interacts with ULM motifs of SF3b155, an U2 snRNP protein. Here, we report a cooperative binding of U2AF65 and the related protein CAPERα to the multi‐ULM domain of SF3b155. In addition, we show that the RS domain of U2AF65 drives a liquid–liquid phase separation that is amplified by intronic RNA with repeated pyrimidine tracts. In cells, knockdown of either U2AF65 or CAPERα improves the inclusion of cassette exons that are preceded by such repeated pyrimidine‐rich motifs. These results support a model in which liquid‐like assemblies of U2AF65 and CAPERα on repetitive pyrimidine‐rich RNA sequences are driven by their RS domains, and facilitate the recruitment of the multi‐ULM domain of SF3b155. We anticipate that posttranslational modifications and proteins recruited in dynamical U2AF65 and CAPERα condensates may further contribute to the complex mechanisms leading to specific splice site choice that occurs in cells.

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Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Cited by 237 publications

References 65 publications

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition

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Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Cited by 237 publications

References 65 publications

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

U2 AF 65 assemblies drive sequence‐specific splice site recognition

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Product

Resources

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U2 AF ⁶⁵ assemblies drive sequence‐specific splice site recognition