The New MPN Protein: Insights from GADD45g Research

  • MPNRF | June 24, 2024

    The fight against blood cancers has taken a significant step forward with new research into the GADD45g gene. Researchers have uncovered surprising insights into the role of GADD45g in myeloproliferative neoplasms (MPNs), providing scientists with a laundry list of related proteins to examine for potential therapeutic targeting. 

    A notable study recently published in Nature Communications by Peiwen Zhang and colleagues at the Chinese Academy of Medical Sciences & Peking Union Medical College uncovered critical insights into the role of the GADD45g protein in MPNs. 

    What is GADD45g?

    The cells in our bodies become defensive when they encounter physiological or environmental stressors. To protect themselves, stressed cells produce stress-related proteins to help with DNA repair and slow or shut down cell division. If the harm experienced by a cell is significant, these stress proteins can also cause cell death, called apoptosis.  

    The GADD45 family of genes express small proteins closely associated with cellular stress. Scientists observed in previous research that the success of various cancers, including solid tumors and blood cancers, depends on disrupting the production of GADD45 proteins. 

    Each member of the GADD45 family is expressed in response to different stressors, playing crucial roles in a cell’s resilience during adverse conditions.  Normally, a member of the protein family called GADD45g slows cell division and growth. It appears that cancer cells must repress the production of the GADD45g protein to ensure survival, particularly in acute myeloid leukemia (AML). 

    Major study findings on GADD45g in MPNs 

    Zhang and colleagues’ new study has yielded several key findings about GADD45g in MPNs:  

    • GADD45g and cancer cell growth: The research found that low levels of GADD45g promote tumor activities in MPN cells. Less GADD45g protein meant more cancer cell division and inflammatory proteins. 
    • GADD45g and disease symptoms: Mice deficient in GADD45g developed symptoms similar to humans with MPNs, such as increased myeloid cells, megakaryocytes (platelet-producing cells), anemia (low red blood cells), and thrombocytosis (high platelet count).  
    • Human MPN relationship: In MPN patients, low GADD45g was associated with increased levels of inflammatory proteins like IL-4 and IL-6. Additionally, when the researchers treated tissue samples from MPN patients with ruxolitinib, a common MPN therapy, it led to an increase in the expression of the GADD45g gene. 
    • GADD45g related proteins: Not only did the researchers identify the relationship between GADD45g and cancer, they also identified a large number of proteins necessary for GADD45g’s activity. 
    • An MPN gene: It is incredibly telling that low GADD45g expression did not affect the production of non-MPN related blood cells. This suggests that scientists have discovered a truly MPN-associated gene.
     

    Impact of JAK2V617F mutation on GADD45g 

    One of the significant findings of the study was the relationship between GADD45g expression and the JAK2V617F mutation, commonly found in MPN patients. The well-known mutation was shown to repress GADD45g gene expression, which in turn contributed to the harmful effects in MPN cells. This highlights the complex interplay between genetic mutations and gene expression in the progression of MPNs. 

    Therapeutic Potential of Restoring GADD45g Gene Expression 

    The research team found that reintroducing GADD45g to mice with MPN symptoms significantly prolonged their survival and reduced disease severity. This suggests that therapies aimed at restoring GADD45g expression could potentially treat MPNs and other related cancers. 

    Future directions 

    The findings underscore the need for further research into methods of increasing GADD45g expression as a therapeutic strategy. Understanding the numerous mechanisms that inhibit GADD45g gene expression and finding medicines to encourage GADD45g or related proteins’ activity could lead to new, more effective cancer therapies. 

    Conclusion

    The findings highlight the importance of conducting additional research and learning how to boost GADD45g expression as a treatment strategy. As researchers continue to explore the complex biology of MPNs, these findings offer hope for improved treatments and better patient outcomes. 

    For more information and updates on MPN research, stay connected with the MPN Research Foundation, dedicated to funding groundbreaking studies and supporting the MPN community. 

    Sources:  

    National Library of Medicine. (n.d.). Genotoxic Stress. ncbi.mlm.nih.gov. Retrieved June 17, 2024, from https://www.ncbi.nlm.nih.gov/medgen/222489 

     Cretu, A., Sha, X., Tront, J., Hoffman, B., & Liebermann, D. A. (2009). Stress sensor Gadd45 genes as therapeutic targets in cancer. Cancer therapy, 7(A), 268–276. 

     Zhang, P., You, N., Ding, Y. et al. Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms. Nat Commun 15, 2989 (2024). 

    Certain medicines listed may not be approved by the US Food and Drug Administration (FDA) for myelofibrosis but are recommended by the National Comprehensive Cancer Network (NCCN). MPN Research Foundation works with NCCN on the creation and updating of its MPN Patient Guidelines.