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It’s Time to Sp(l)ice Things Up!

December 11, 2023
Diego Adrianzen Herrera, MD, MSc, (@diegoah66) 
Division of Hematology and Oncology, Larner College of Medicine, University of Vermont, Burlington

In cell biology, RNA splicing is the process of removing introns from transcribed precursor messenger RNA (mRNA) to transform it into mature (spliced) mRNA. Alternative splicing, which ordinarily allows a single gene to code for multiple proteins, has been recognized as a commonly dysregulated process in human cancer. Variants in SF3B1, the largest subunit in the spliceosome factor 3b complex, have been commonly detected across various forms of hematologic neoplasia including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL), as well as pre-malignant conditions such as clonal hematopoiesis. So what would happen if mis-splicing from mutant SF3B1 was corrected? Could aberrant splicing be targeted therapeutically?  

The abstract “Synthetic Introns Identify the Novel RNA Splicing Factor GPATCH8 As Required for Mis-Splicing Induced by SF3B1 Mutations,” from yesterday’s Plenary Scientific Session, highlighted the type of discovery that moves the field forward — one that could make targeting splicing a reality. Salima Benbarche, PhD, a research scholar at the Omar Abdel-Wahab Lab at Memorial Sloan Kettering Cancer Center in New York, walked us through the discovery of GPATCH8, a human protein largely unexplored to date, as an RNA splicing factor whose expression is required for the aberrant splicing and consequent neoplastic pathogenesis caused by variants in SF3B1 

Dr. Benbarche and colleagues engineered a synthetic intron to interrupt the coding of a constitutively fluorescent protein and made use of how its expression differed due to aberrant splicing to differentiate between mutant and wild-type (WT) SF3B1 cells. Using a positive enrichment CRISPR screen, they identified GPATCH8 as a gene whose loss corrected SF3B1 mis-splicing, suggesting its role in the aberrant function of mutant SF3B1. They then recognized that GPATCH8 had characteristics of RNA splicing factors and activated RNA helicases, much like SUGP1, a splicing factor previously shown to be implicated in mis-splicing in SF3B1-mutant cancers by disrupting the interaction between SF3B1 and the RNA helicase DHX15.1 Further experiments demonstrated similarities between GPATCH8 and SUGP1. They both target intron sequences, denoting a role in splicing; their deletion corrects alterations caused by SF3B1-mutant splicing; and they both interact with DHX15. Dr. Benbarche’s team thus concluded that GPATCH8 competed with SUGP1 for interaction with DHX15. 

That’s impressive work, but is there a potential therapeutic implication of this discovery? It turns out there might be. The investigators demonstrated that GPATCH8 deletion corrects aberrant RNA splicing caused by the mutant SF3B1 complex. First, they showed that bone marrow samples from SF3B1-mutant mice exhibited impaired hematopoietic colony formation in vitro when compared with wildtype (WT) samples. Subsequently, they showed that silencing GPATCH8 phenotypically rescued the colony formation capacity of samples from SF3B1-mutant mice. Finally, they proved that CRISPR knock-in of an SF3B1 mutation in adult human CD34-positive cells impaired erythroid development, and that this effect was reversed by GPATCH8 deletion. Together, these findings move the epigenetics field forward, offering the hope of a new therapeutic strategy: correcting genetic splicing errors to treat hematologic malignancies.  

Interestingly, previous work from Dr. Abdel-Wahab’s laboratory had already recognized the therapeutic potential of splicing modulation in spliceosome-mutant malignancies.2 We were fortunate to have the chance to discuss this potential with Dr. Abdel-Wahab himself, who broke the ice by admitting: “I recognize that this abstract is quite far from a clinical abstract and deals with an area of biology that many in the audience may not be familiar with.”  

Despite this, he comprehensively broke down the scientific steps leading to this discovery, even commenting on the genesis of the state-of-the technology used: The synthetic intron technology and platform that was the basis for this abstract was originally conceived in a collaboration with the lab of Dr. Rob Bradley (Fred Hutchinson Cancer Research Center) and my lab at Memorial Sloan Kettering Cancer Center,” listing Dr. Benbarche as “one of the key inventors.”  

When asked to project how this work could potentially change the therapeutic landscape in the future, he replied: “The original idea behind the synthetic intron technology is that the RNAs themselves could be delivered as a therapy to selectively eliminate RNA splicing factor mutant diseased cells.” He added, “this is an approach we are actively pursuing now by trying to deliver the RNAs in vivo,” and concluded promisingly, “now, in this abstract, we have also identified a potentially druggable regulator of mutant SF3B1 … these therapeutic approaches could be important for the many patients with CLL, MDS, AML, and other myeloid malignancies carrying SF3B1 mutations.”  

Indeed, we are inspired by this outstanding work and hope, too, that it will generate new targeted drugs with the potential to help many, many more patients with hematologic malignancies. Who knew that all we needed was just a little more … sp(l)ice? 

1 Zhang J, Huang J, Xu K, et al. DHX15 is involved in SUGP1-mediated RNA missplicing by mutant SF3B1 in cancer. Proc Natl Acad Sci U S A. 2022;119(49):e2216712119. 

2 Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497-504. 

Dr. Adrianzen Herrera indicated no conflicts of interest.   

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