Despite distinct clinical entities, the myeloproliferative neoplasms (MPN) share morphological similarities, propensity to thrombotic events and leukemic evolution, and a complex molecular pathogenesis. Well-known driver mutations, JAK2, MPL and CALR, determining constitutive activation of JAK-STAT signaling pathway are the hallmark of MPN pathogenesis. Recent data in MPN patients identified the presence of co-occurrence somatic mutations associated with epigenetic regulation, messenger RNA splicing, transcriptional mechanism, signal transduction, and DNA repair mechanism. The integration of genetic information within clinical setting is already improving patient management in terms of disease monitoring and prognostic information on disease progression. Even the current therapeutic approaches are limited in disease-modifying activity, the expanding insight into the genetic basis of MPN poses novel candidates for targeted therapeutic approaches. This review aims to explore the molecular landscape of MPN, providing a comprehensive overview of the role of drive mutations and additional mutations, their impact on pathogenesis as well as their prognostic value, and how they may have future implications in therapeutic management.

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd–Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.

Major disease complications for patients with essential thrombocythemia (ET) include thrombosis and fibrotic or leukemic transformation. Calreticulin (CALR) mutation type 1 frequencies in ET are estimated between 7% and 11% and ET patients carrying CALR type 1 mutation are associated with lower risk of thrombosis but higher risk of myelofibrosis transformation compared to ET patients with JAK2 mutation. Leukemic transformation rates at 20 years are estimated at less than 5% for ET and risk factors for leukemic transformation are advanced age, thrombosis history, leukocytosis, and anemia. Amongst the subtypes of blast phase myeloproliferative neoplasms, acute promyelocytic leukemia is extremely rare. Herein, we present a case of a promyelocytic blast crisis of post-ET myelofibrosis with associated life-threatening splanchnic vein thrombosis. This case suggests that inflammation plays a key role in thrombotic events and fibrotic/leukemic transformation in ET patients, regardless the molecular landscape.