GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies Journal Article
| Authors: | Benbarche, S.; Pineda, J. M. B.; Galvis, L. B.; Biswas, J.; Liu, B.; Wang, E.; Zhang, Q.; Hogg, S. J.; Lyttle, K.; Dahi, A.; Lewis, A. M.; Sarchi, M.; Rahman, J.; Fox, N.; Ai, Y.; Mehta, S.; Garippa, R.; Ortiz-Pacheco, J.; Li, Z.; Monetti, M.; Stanley, R. F.; Doulatov, S.; Bradley, R. K.; Abdel-Wahab, O. |
| Article Title: | GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies |
| Abstract: | Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers. © 2024 The Author(s) |
| Keywords: | controlled study; protein expression; leukemia; unclassified drug; gene mutation; human cell; genetics; mutation; nonhuman; flow cytometry; quality control; animal cell; mouse; animal; metabolism; animals; mice; cd34 antigen; clinical assessment; animal experiment; animal model; protein; intron; introns; pathology; proteomics; stem cell; dead box protein; rna binding protein; rna; dead-box rna helicases; rna-binding proteins; hematologic malignancy; hematologic neoplasms; regulatory mechanism; messenger rna; adenosine; phosphoproteins; hematopoiesis; gene silencing; pathogenicity; adenosine triphosphatase; rna helicase; rna helicases; phosphoprotein; glycine; uridine; hematologic disease; rna splicing; myelodysplastic syndromes; splicing; fusion protein; hek293 cells; splicing defect; adenosine deaminase; antagonistic effect; guide rna; sf3b1 protein; humans; human; female; article; sf3b1; methylcellulose; rna splicing factor; rna splicing factors; sf3b1 protein, human; hek293s cell line; dhx15; g-patch domain; gpatch8; sugp1; ascorbate peroxidase; dhx15 protein; g patch domain containing protein 8; k666n protein; k700e protein; kiaa0100 protein; map3k7 protein; ppm1m protein; psme4 protein; r625h protein; smurf2 protein; surp protein; zdhhc16 protein; zmym2 protein; sf3b1 protein, mouse |
| Journal Title: | Molecular Cell |
| Volume: | 84 |
| Issue: | 10 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2024-05-16 |
| Start Page: | 1886 |
| End Page: | 1903.e10 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2024.04.006 |
| PUBMED: | 38688280 |
| PROVIDER: | scopus |
| PMCID: | PMC11102302 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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