Genetic basis and molecular profiling in myeloproliferative neoplasms

• Published in: Blood Vol. 141; no. 16; pp. 1909 - 1921
• Main Authors: Luque Paz, Damien, Kralovics, Robert, Skoda, Radek C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.04.2023
• Subjects: Calreticulin - genetics; Calreticulin - metabolism; Humans; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Mutation; Myeloproliferative Disorders - metabolism; Polycythemia Vera - genetics; Primary Myelofibrosis - genetics; Receptors, Thrombopoietin - genetics; Receptors, Thrombopoietin - metabolism; Thrombocythemia, Essential - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022017578

[Display omitted] BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are clonal diseases originating from a single hematopoietic stem cell that cause excessive production of mature blood cells. The 3 subtypes, that is, 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 1 of 3 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, those referred to as being “triple negative,” none of the known driver gene mutations can be detected. The common theme between the 3 driver gene mutations and triple-negative MPN is that the Janus kinase–signal transducer and activator of transcription (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. The limiting factor that determines the frequency at which MPN disease develops with a long latency is not the acquisition of driver gene mutations, but rather the expansion of the clone. Factors that control the conversion from clonal hematopoiesis to MPN disease include inherited predisposition, presence of additional mutations, and inflammation. The full extent of knowledge of the mutational landscape in individual MPN patients is now increasingly being used to predict outcome and chose the optimal therapy. Our knowledge about the biology of myeloproliferative neoplasms (MPNs) has exploded in the last 20 years, and this increased knowledge has led to advances in therapy. Introduced by Associate Editor Mario Cazzola, this Review Series brings readers up to date on our understanding of the natural history of the classical MPNs—polycythemia vera, essential thrombocythemia, and myelofibrosis—and the approaches to diagnosis, prognostication, and treatment for patients with these conditions.