Study Finds Ruxolitinib May Slow Fibrosis Progression in Myelofibrosis

Through proteomic screening, researchers have identified chemokine Platelet Factor 4 (PF4/Cxcl4) as a key driver of myelofibrosis (MF). Their findings, published in Nature, further the clinical understanding of the pathological mechanisms underlying the risk and development of MF, and provide insights into the capabilities of ruxolitinib [Jakafi; Incyte Corp] to reduce fibrosis in patients with MF.¹

According to their findings, ruxolitinib, a JAK inhibitor indicated for the treatment of patients with high-risk MF, reduced the abnormal expression of PF4. Image Credit: © Ployker - stock.adobe.com

MF is a rare, fatal myeloproliferative neoplasm (MPN) characterized by the overproduction hematopoietic stem cells, resulting in increasingly reduced red blood cell production. Despite increased knowledge of the genomic landscape of MPNs, there is little understanding of the mechanisms underlying the dysfunctional interaction between abnormal megakaryocytes (Mk) and stromal cells, which contributes to the excessive buildup of fibrous tissues and scarring within the bone marrow. This further impairs normal blood cell production.^2,3

To understand the alterations in signaling pathways, as well as protein changes in Mks, platelets, and bone marrow (BM) cells, the researchers used mass-spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis. The results showed that PF4/Cxcl4, a chemokine that plays a role in blood cell production, inflammation, and T-cell function, was up regulated in all proteomes.¹

The researchers found that PF4 is rapidly absorbed by glycosaminoglycans (GAGs) on the surface of stromal cells, causing cellular changes that contribute to the progression of fibrosis. Additionally, high levels of thrombopoietin (TPO) were linked to the sustained overproduction of PF4 in Mks. Silencing the Cxcl4 gene led to reduced fibrotic activity of stromal cells in high TPO conditions, suggesting that PF4 encoded by Cxcl4 plays a significant role in promoting fibrosis.¹

Extensive uptake of PF4 and altered GAG accumulation were detected in both Romiplostim-treated, JAK2V617F mice and bone marrow (BM) biopsies from patients with MPN. In the patients’ BM samples, PF4 levels and Cxcl4 expression were elevated; however, this was only seen in cases with advanced fibrosis. By inhibiting GAGs in mice and thereby reducing fibrosis, the researchers propose that disrupting the interaction between PF4 and GAGs could potentially slow fibrosis progression in MPNs.¹

According to their findings, ruxolitinib, a JAK inhibitor indicated for the treatment of patients with high-risk MF, reduced the abnormal expression of PF4, leading to decreased fibrosis. Ruxolitinib is a commonly used treatment for MF that was approved in 2011 by the FDA; however, the study results provide a deeper understanding of its mechanism of action and impact on fibrosis. With further research, there is potential for the use of ruxolitinib in combination with agents that inhibit the interaction between PF4 and GAGs, offering patients more tailored approaches to treatment.^1,4

The study shows that ruxolitinib not only plays a crucial role symptom management, but it may also help address the underlying fibrotic changes that often lead to severe complications. Future research is needed to investigate the long-term impact of the treatment, its efficacy and safety, and its potential use as a combination treatment in different patient populations across disease stages. With continued study, there is increased potential for more effective treatment strategies that lead to improved patient care.

REFERENCES

1. Capitanio D, Calledda FR, Abbonante V, et al. Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis. Leukemia. July 18, 2024. doi: 10.1038/s41375-024-02354-z

2. Study demonstrates safety, efficacy of luspatercept for mf-related anemia. Pharmacy Times. September 19, 2024. Accessed September 24, 2024. https://www.pharmacytimes.com/view/study-demonstrates-safety-efficacy-of-luspatercept-for-mf-related-anemia

3. PF4 platelet factor 4 [ Homo sapiens (human) ]. National Library of Medicine. September 19, 2024. Accessed September 24, 2024. https://www.ncbi.nlm.nih.gov/gene/5196

4. Ruxolitinib. National Library of Medicine. June 5, 2023. Accessed September 24, 2024. https://www.ncbi.nlm.nih.gov/books/NBK570600/#:~:text=Go%20to%3A-,Mechanism%20of%20Action,site%20on%20JAK1%20and%20JAK2