Effect of mutation on diagnosis, risk stratification, and treatment decisions in Philadelphia-negative myeloproliferative neoplasms

Abstract

Since the discovery of the activating mutation of JAK2, known as JAK2V617F, our understanding of mutation profiles, and the biological significance of this mutation in Philadelphia-negative (Ph-) MPNs has drastically changed over the last decade. Mutations of the thrombopoietin receptor MPL and chaperone protein calreticulin gene also induce aberrant activation of JAK and downstream molecules, including STAT proteins, and contribute to the development of MPNs. Mutations of the genes JAK2, MPL, and calreticulin are referred to as “driver mutations” for MPNs. Recent advances in genetic tests using next-generation sequencing have revealed that in addition to driver mutations, approximately half of Ph-MPN patients have at least one more mutation. These genes serve as components of spliceosomal machinery, DNA methylation modifiers, and regulators of histone function. Mutations of these genes are known as “non-driver mutations” and are thought to be involved in modifying the disease phenotype and progression of Ph-MPNs. In addition to its biological significance, the mutation profile also provides numerous pieces of important information for the clinical aspects of Ph-MPNs. In this study, the role of molecular profiling of Ph-MPNs for diagnosis, risk evaluation, and treatment decisions was discussed.