A KMT2C loss-of-function mutation in a JAK2-negative polycythemia vera-like myeloproliferative neoplasm: a case...

Polycythemia vera (PV) is a clonal myeloproliferative neoplasm (MPN) typically defined by JAK2 mutations. JAK2-negative presentations pose significant diagnostic challenges and likely harbor a spectrum of molecular drivers that remain incompletely characterized.

We report a case of JAK2-negative PV-like MPN in a 53-year-old male presenting with erythrocytosis, suppressed erythropoietin, panmyelotic bone marrow morphology, and splenic vein thrombosis. Standard JAK2 V617F and exon 12 analyses were negative. Next-generation sequencing (NGS) identified a KMT2C nonsense variant (c.2961C>G, p.Tyr987*) at a variant allele frequency (VAF) of 21%, providing molecular evidence of clonality. The clinical course was complicated by intermittent hydroxyurea non-adherence with marked hematocrit fluctuations; dose optimisation from 1 g to 2 g daily achieved stable hematological control.

This case adds to the emerging molecular landscape of JAK2-negative MPNs by identifying KMT2C loss-of-function as a clonal marker in a patient with a JAK2-negative PV-like MPN phenotype. Whether KMT2C p.Tyr987* contributes causally to the erythroid-biased expansion or represents an accompanying clonal event warrants functional investigation. Comprehensive genomic profiling is essential when canonical driver mutations are absent, and strict adherence to cytoreductive targets remains critical to prevent thrombotic complications.