29 Apr Hebrew University Researchers Identify RNA Dicing as Key Driver of JAK1 Oncogenic Activity in Endometrial Cancer

Dr. Yuval Malka, PhD

MedicalResearch.com Interview with
Dr. Yuval Malka, PhD
Faculty of Medicine Hebrew University and
Founder & CEO of Modular Therapeutics BV and
Dr. William Faller PhD
University of Bristol

discussing their new study on RNA dicing — a fundamental mechanism that generates multiple functional protein outputs from a single mRNA molecule — and its implications for cancer biology and therapeutics.

MedicalResearch.com: What is the background for this study?

Response: This study is a follow-up to previous work published in recent years (Malka et al., Nature Communications 2017; Malka et al., Molecular Cell 2022), in which we discovered that the mRNA of thousands of genes can be further processed into smaller fragments that translate into shorter proteins. On one hand, this finding helps bridge the gap between our understanding of the transcriptome – traditionally limited to ~20,000 genes and the proteome, which contains hundreds of thousands to potentially millions of distinct protein and peptide isoforms. On the other hand, those earlier studies did not provide sufficient biological insight into this extensive and robust process.

The current study represents the third part of this trilogy, introducing a new concept in RNA biology termed “RNA dicing.” We show that RNA dicing in eukaryotic systems enables the production of multiple functional protein outputs from a single mRNA molecule. How does this work? Most proteins consist of several domains, each with a distinct function, for example, mediating protein–protein interactions, determining subcellular localization, or carrying catalytic activity. We demonstrate that RNA dicing selectively removes portions of the mRNA template, resulting in the translation of shorter proteins lacking specific domains. This leads to substantial changes in protein function, localization, and interaction partners. In simple terms, RNA dicing mediates modular gene expression.

MedicalResearch.com: What are the main findings?

Response: Focusing on JAK1, we show that RNA dicing generates a novel protein isoform with properties distinct from the canonical JAK1 protein. In the diced isoform, only the terminal kinase domain is translated. In contrast, the canonical JAK1 protein contains four major domains: three upstream domains responsible for membrane localization, protein interactions, and a pseudokinase domain that inhibits kinase activity. When dicing occurs, the resulting isoform lacks these regulatory domains, allowing it to translocate to the nucleus and function more robustly due to the absence of inhibitory regulation.

These findings provide a high-resolution understanding of how JAK1 functions dynamically. Importantly, they also have major clinical implications. A longstanding question in cancer biology is why certain genes, such as JAK1, can act as tumor suppressors in some contexts and oncogenes in others. Our study identifies RNA dicing as the transition mechanism between these states. Specifically, dicing shifts expression from a tumor-suppressive canonical isoform to a truncated isoform with oncogenic properties.

Furthermore, a substantial proportion of women with endometrial cancer harbor frameshift mutations in JAK1. These mutations are typically classified as loss-of-function because they disrupt canonical protein translation. However, clinically, these patients often exhibit poor prognosis and high tumor grade. Our model explains this paradox: the mutation selectively disrupts translation of the tumor-suppressive isoform while leaving the oncogenic isoform unaffected, as the mutation lies upstream of the truncated region. This imbalance favors oncogenic activity and contributes to disease progression.

MedicalResearch.com: Is this process similar to how CRISPR technology works? What could turn on the oncogenic JAK1 isoform? HPV viruses?

Response: In contrast to CRISPR technology – which adapts a bacterial system for gene editing, the RNA dicing process we describe is a fundamental, intrinsic mechanism that likely occurs in most human cells and across many organisms. It is a natural process that modifies mRNA to generate multiple protein isoforms from a single gene, thereby expanding functional diversity.

We have shown, and continue to study, how RNA dicing is dynamically regulated. For example, JAK1 plays a critical role in the immune system. In our study, we examined JAK1 dicing in macrophages following differentiation into a pro-inflammatory state. Under these conditions, JAK1 signaling is central, and we observed a significant increase in RNA dicing, enabling the production of protein variants required for appropriate signaling responses.

In the context of endometrial cancer, we demonstrated that mutations can selectively silence the tumor-suppressive isoform, disrupting the natural balance between isoforms and promoting cancer progression. Ongoing work aims to identify the upstream triggers of dicing, which may include cellular stress, signaling pathways, or potentially viral influences, although this remains to be fully explored.

MedicalResearch.com: What should readers take away from your report?

Response: This study demonstrates that genes are not static, monolithic entities but rather modular and dynamic systems capable of diversifying their biological outputs. While we focused on JAK1 as a case study, this fundamental mechanism likely applies broadly across the genome.

Our findings provide meaningful insights into JAK1 biology, but they also open the door to many additional discoveries. We are currently conducting several studies that extend this concept and offer solutions to biological questions that existing models cannot adequately address.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: This work extends beyond basic science into clinical applications. In the final part of the study, we demonstrate how these insights can inform therapeutic strategies. JAK1 is one of the most targeted kinases in the clinic, with several FDA-approved inhibitors. However, based on current models, treating patients who carry loss-of-function JAK1 mutations with JAK1 inhibitors would seem counterintuitive.

Our findings suggest the opposite. We show that endometrial cancer cells harboring these mutations respond more effectively to JAK1 inhibitors than cells expressing normal JAK1.
This discovery has been protected by intellectual property (PCT/NL2025/050071) and has led to the establishment of a company in the Netherlands (Modular Therapeutics B.V.), which has secured pre-seed funding to develop new therapeutic approaches for patients with these mutations.

Disclosures: I am the inventor of the intellectual property mentioned above and the founder of Modular Therapeutics, a spin-off company from the Netherlands Cancer Institute.

Citation:
van der Kammen R, Yakov O, Ju S …
RNA dicing promotes the expression of an oncogenic JAK1 isoform
Cell Reports, 2026; 45

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Last Updated on April 29, 2026 by Marie Benz MD FAAD