Triple Negative Myeloproliferative Neoplasms - Sometimes Driver Mutations Stay Low-Key in Plain Sight

摘要

Triple Negative Myeloproliferative Neoplasms (TN MPNs) have recently emerged as a separate molecular entity, being characterized by the absence of mutations in the 3 driver genes that represent the hallmarks of classical BCR-ABL1 negative myeloproliferative neoplasms (MPNs): JAK2, calreticulin (CALR) and thrombopoietin receptor (MPL/TpoR). It seems that this entity has a different clinical outcome than other MPN categories although pathologic activation of JAK/STAT signaling is also at the core of the disease. A deeper exploration of the genetic background of TN MPNs reveals a heterogeneous molecular profile that consists either of canonical MPN driver mutations with very low allele burden or detected only at the level of platelet ARN, non-canonical MPL and JAK2 mutations of either somatic or germ-line origin, or also mutations in other non-MPN-driver genes. Polyclonal hematopoiesis is present in some cases suggesting that those are more likely benign disorders of platelet production, like hereditary thrombocytosis, than MPNs. A mutational analysis beyond the routine molecular investigations is often necessary to unravel the “low-key” drivers of the TN MPNs.