Genetic basis and molecular profiling in myeloproliferative neoplasms

Abstract

BCR::ABL1-negative myeloproliferative neoplasms (MPN) are clonal diseases originating from a single hematopoietic stem cell (HSC) that cause excessive production of mature blood cells. The three subtypes polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are diagnosed according to the World Health Organization (WHO) and International Consensus Classification (ICC) criteria. Acquired gain-of-function mutations in one of three disease driver genes, JAK2, CALR and MPL are the causative events that can alone initiate and promote MPN disease without requiring additional cooperating mutations. JAK2-p.V617F is present in >95% of PV patients, and also in about half of the patients with ET or PMF. ET and PMF are also caused by mutations in CALR or MPL. In ~10% of MPN patients, called "triple negative", none of the known driver gene mutations can be detected. The common theme between the three driver gene mutations and "triple-negative" MPN is that the JAK/STAT signaling pathway is constitutively activated. We review the recent advances in our understanding of the early events after the acquisition of a driver gene mutation. Not the acquisition of driver gene mutations, but rather the expansion of the clone is the limiting factor that determines the frequency at which MPN disease develops with a long latency. Factors that control the conversion from clonal hematopoiesis to MPN include inherited predisposition, presence of additional mutations and inflammation. The complete knowledge of the mutational landscape in individual MPN patients is now increasingly being used to predict outcome and chose the optimal therapy.