Understanding Triple Negative Myeloproliferative Neoplasms and Identifying Molecular Drivers

Purpose of Review: Triple-negative (TN) myeloproliferative neoplasms (MPNs), defined by the absence of canonical driver JAK2, CALR and MPL mutations, represent a heterogeneous and still poorly understood subgroup of chronic myeloid neoplasms. This review summarizes current knowledge on characteristics and molecular landscape of TN MPNs. Recent Findings: Although TN MPNs share clinical and morphological features with classic forms of primary myelofibrosis and essential thrombocythemia, their clinical behavior varies widely, from indolent in TN essential thrombocythemia to aggressive in TN myelofibrosis. Recent next-generation sequencing analyses have identified mutations affecting epigenetic regulation, RNA splicing, and various signaling pathways (e.g., TET2, ASXL1, SRSF2, EZH2, SETBP1), thereby underscoring the substantial biological complexity within these subgroups. Summary: This review provides an updated overview of the molecular landscape, clinicopathological features, and prognostic implications of TN MPNs, with a focus on the molecular mechanisms that have been uncovered through recent advances in diagnostic and genomic profiling techniques. Understanding the underlying disease mechanisms may lead to personalized treatments and better risk assessment for these patients.