Inflammation and bone marrow fibrosis: novel immunotherapeutic targets

Abstract

Purpose of review Myelofibrosis (MF) is primarily driven by constitutive activation of the Janus kinase/signal transducer of activators of transcription (JAK/STAT) pathway. While JAK inhibitors have shown to alleviate disease symptoms, their disease-modifying effects in MF are limited. The only curative treatment remains allogeneic stem cell transplantation, which can be applied to a minority of patients. As a result, there is a need to explore novel targets in MF to facilitate appropriate drug development and therapeutic pathways. Recent findings Recent research has focused on identifying novel signals that contribute to the abnormal cross-talk between hematopoietic and stromal cells, which promotes MF and disease progression. Inflammation and immune dysregulation have emerged as key drivers of both the initiation and progression of MF. A growing number of actionable targets has been identified, including cytokines, transcription factors, signalling networks and cell surface-associated molecules. These targets exhibit dysfunctions in malignant and nonmalignant hematopoietic cells, but also in nonhematopoietic cells of the bone marrow. The study of these inflammation-related molecules, in preclinical models and MF patient's samples, is providing novel therapeutic targets. Summary The identification of immunotherapeutic targets is expanding the therapeutic landscape of MF. This review provides a summary of the most recent advancements in the study of immunotherapeutic targets in MF.

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

“…JAK inhibitors are considered anti-inflammatory drugs that have been successfully used in the treatment of rheumatoid arthritis, inflammatory bowel diseases, and COVID-19 [162]. However, treatments that specifically target inflammatory processes have not achieved significant progress in MF [163][164][165]. On the other hand, interferon alpha (IFN-α) is currently used for ET and PV and has been found to effectively suppress neoplastic clone [166] in a driver mutation-dependent manner [167,168], presumably affecting the proliferation and differentiation dynamics of hematopoietic stem/progenitor cells harboring mutations [169,170], thus depleting the neoplastic clone at the stem cell level.…”