Exploring the Molecular Landscape of Myelofibrosis, with a Focus on Ras and Mitogen-Activated Protein (MAP) Kinase Signaling

SIMPLE SUMMARY: Myelofibrosis is a disease arising from bone marrow driven by mutations in stem cells, which results in progressive failure of marrow production in red and white blood cells as well as platelets. Patients can also develop leukemia (a cancer of white blood cells) over time. While the only cure is a bone marrow transplant, many patients are not candidates and require treatment for symptomatic disease. The most common therapies target a protein known as “Jak” but resistance to these agents is common, making the exploration of alternative mechanisms for how such resistance manifests essential. Beyond Jak, another emerging yet under-explored target in myelofibrosis is a group of proteins known as “Ras/MAP Kinase”. The aim of this review is to present research into Ras/MAP Kinase signaling and its role in myelofibrosis, which we hope will expand how providers view and target this disease, ultimately improving the lives of patients. ABSTRACT: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm (MPN) characterized clinically by cytopenias, fatigue, and splenomegaly stemming from extramedullary hematopoiesis. MF commonly arises from mutations in JAK2, MPL, and CALR, which manifests as hyperactive Jak/Stat signaling. Triple-negative MF is diagnosed in the absence of JAK2, MPL, and CALR but when clinical, morphologic criteria are met and other mutation(s) is/are present, including ASXL1, EZH2, and SRSF2. While the clinical and classic molecular features of MF are well-established, emerging evidence indicates that additional mutations, specifically within the Ras/MAP Kinase signaling pathway, are present and may play important role in disease pathogenesis and treatment response. KRAS and NRAS mutations alone are reportedly present in up to 15 and 14% of patients with MF (respectively), and other mutations predicted to activate Ras signaling, such as CBL, NF1, BRAF, and PTPN11, collectively exist in as much as 21% of patients. Investigations into the prevalence of RAS and related pathway mutations in MF and the mechanisms by which they contribute to its pathogenesis are critical in better understanding this condition and ultimately in the identification of novel therapeutic targets.