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

Simple Summary Myelofibrosis refers to fibrosis in the bone marrow associated with certain bone marrow cancers. It is a characteristic of primary myelofibrosis and may develop later in other bone marrow cancers with overproduction of blood cells, such as polycythemia vera and essential thrombocythemia. It has been confirmed that mutations in three key genes, Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia oncogene (MPL), can increase the activity of blood-producing cells, make them grow more actively, and are associated with the development of myelofibrosis. Approximately 80% of myelofibrosis cases carry additional mutations that often involve proteins that control how genes are turned on and off. The presence of mutations provides evidence of a cancerous process. The order in which these mutations occur can influence how the disease manifests. Studies have shown that fibrosis is secondary to the cancerous process and is closely linked to abnormal cell growth driven by mutations. Sophisticated scoring systems have been developed to guide treatment decisions. Specific mutations and genetic changes significantly affect the scores and survival of individual patients. Currently, common treatment involves JAK inhibitors, which can help improve clinical symptoms; however, only a small number of patients show significant alleviation in the biology of the malignant process. New treatments being explored in clinical trials include drugs that target the regulation of genes and substances that modulate the immune system or inflammatory processes. Combining these with JAK inhibitors shows promising results, especially in patients with complex genetic profiles. In the future, by studying more genes, it is expected that researchers will uncover the reasons behind cases where mutations are not found in the three key genes and understand how genetic changes are connected to variable disease presentations, ultimately guiding personalized treatment plans for better outcomes with a chance for cures.Abstract Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.