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Interleukin-1: the unexpected foe implicated in the inflammatory evolution of bone marrow fibrosis

Pioneering research into the chronic inflammation often seen in some blood cancers has identified a promising treatment approach for myelofibrosis, a potentially deadly bone marrow cancer. New research from UVA Cancer Center identifies a major contributor to the relentless inflammation associated with a group of blood cancers called myeloproliferative neoplasms. These tumors cause the bone marrow to make too many blood cells. This leads to symptoms such as headache, fever, fatigue, weakness, bone pain, bleeding and enlarged spleen. The pharmacological JAK2 inhibitors, ruxolitinib and fedratinib, are currently approved therapies for myelofibrosis but do not significantly reduce bone marrow fibrosis. Hence, the scientists believe that factors other than JAK2 activation could be involved in the development of the condition. A bone marrow transplant is the only potential cure now available for myelofibrosis.

But such a procedure is very taxing on the body and is associated with many complications, making it risky for older patients. Since not all patients are eligible for bone marrow transplantation, new treatment options are badly needed. The research provides new insights into how bone marrow cancer cells promote the development of myelofibrosis, where chronic inflammation (inflammation) is frequently seen. Patients with this condition often show increased levels of inflammatory cytokines; gene expression analysis also confirms the enrichment of inflammatory and immune system gene signatures in myelofibrotic stem cells. Additionally, inflammation has been associated with progression to bone marrow fibrosis. In this new investigation, researchers have identified a cytokine called interleukin-1 (IL-1), which may contribute to the progression of myelofibrosis.

The research team found that IL-1 is crucial for the development of myelofibrosis. Administered to JAK2 kinase (V617F) mutant laboratory mice accelerated bone marrow sclerosis and fueled excess blood cell production. Its reduction, however, had the opposite effect. This was somewhat surprising to the team, as previous studies have suggested that disrupting IL-1 signaling has no significant impact on normal hematopoietic development. However, IL-1 directly expands bone marrow mesenchymal cells, which can transform and mature into fibroblasts, thereby contributing to bone marrow fibrosis. The researchers also looked at interleukin-1 levels in human patients. They found that these patients showed elevated levels of two forms of IL-1, reinforcing the case that either IL-1 or its are promising treatment targets. They believe that IL-1 sends signals that amplify body inflammation by promoting bone marrow sclerosis.

They were able to block that process in lab mice using an anti-IL1 monoclonal antibody, dramatically reducing marrow scarring. Furthermore, the effects of IL-1 appear to be mediated by direct cellular signals (p38, JNK, NF-kB proteins), without the intervention of other factors such as TGF-beta which is a known tissue fibrosis inducing agent. Scientists may be able to adapt this approach or use other means to block IL-1 and stimulate similar benefits in human patients, although much more research is needed. Targeting this cytokine could prevent myelofibrosis from progressing and could spare the bone marrow from converting into ‘dead’ tissue that no longer produces blood cells. Consistent with this finding, a previous study suggested that inhibition of IL-1 signaling using the IL-1R antagonist (Anakinra) enhanced the clearance of chronic myeloid leukemia (CML) malignant stem cells.

The team is developing a strategy to determine the best way to target the IL-1 network, whether with a direct inhibitor, an antagonist of its receptor or by specifically affecting the cellular pathways activated by this cytokine.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry

Scientific references

Rai S et al. Nat Commun. 2022 Sep 13; 13(1):5346.

Rahman MF et al. Nat Commun. 2022 Sep 13; 13(1):5347.

Gangat N, Tefferi A. Br J Haematol. 2020; 191(2):152-70.

Fisher DAC, Miner CA et al. Leukemia 2019; 33(8):1978.

Vainchenker W, Kralovics R. Blood. 2017; 129:667–679.

Pietras EM et al. Nature Cell Biol. 2016; 18:607–618.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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