Singular mutations in either JAK2, CALR or MPL genes are the most frequent drivers of the myeloproliferative neoplasms (MPN) with variants in other myeloid-associated genes contributing to disease phenotype and clinical course. MPN molecular diagnostic algorithms can be either sequential or simultaneous with each technology employed possessing its own sensitivities, specificities and clinical applicability [1]. An increasingly recognised, minor subgroup of MPN patients, particularly those with essential thrombocythemia (ET) and primary myelofibrosis (PMF), harbor two driver mutations [2]. Prior evidence suggests a second driver mutation occurs more commonly in low variant allele frequency (VAF) JAK2 V617F-mutated MPN with the presence of two mutations affecting the phenotype such as a higher platelet count [3,4].

In order to evaluate the incidence and molecular diversity of the dual driver phenomenon in the Irish MPN population, an audit was performed on all requests received at a center for molecular diagnosis of MPN. Mutations in JAK2 (exons 12 and 14), CALR (exon 9), and MPL (exon 10) were identified using a previously described single-molecule, molecular inversion probe-based next-generation sequencing (NGS) methodology [5,6]. From March 2023 to November 2025, 1275 consecutive, new patients were identified with either JAK2 V617F (n = 1011; 79.3%), JAK2 exon 12 (n = 12; 0.9%), CALR exon 9 (n = 168; 13.2%) or MPL exon 10 (n = 84; 6.6%) mutations. This cohort consisted of 665 females and 610 males with a median age of 68 years (range: 21–97 years). Of these 1275 patients, thirteen (1.0%) were identified with ET (n = 12) or PMF (n = 1) with two driver mutations. This group comprised eight females and five males with a median age at presentation of 71 years (range: 61–89 years) and a median presenting platelet count of 853 × 109/L (range: 562–1244 × 109/L) (Table 1). Of the 26 mutations in 13 patients, eleven (42.3%) were JAK2 V617F, eleven (42.3%) were in MPL exon 10 and four (15.4%) were in CALR exon 9. Of the eleven patients with a JAK2 V617F, seven (63.6%) had a VAF ≤5% (Table 1).

In this European cohort, 1% of MPN patients presented with dual driver mutations, similar to the recently described rate of 1.5% [7]. The association of dual driver mutations in patients with a low JAK2 V617F VAF is also confirmed [8,9]. In agreement with a proposal that a platelet count higher than 700 × 109/L acts as a general discriminator for identifying dual driver mutations [4], only three of thirteen patients presented with a lower platelet count. The relatively small size and short follow-up of this cohort preclude any clinical correlation. In MPN patients with a single driver mutation, MPL exon 10 mutations are present in approximately 5% and 9% of patients with ET and PMF respectively with the W515L allele being most prevalent. In contrast, MPL exon 10 mutations account for >40% of variants in this dual-driver population; these include the less common MPL S505N, W515R, and W515A mutations. This study provides confirmation of the prevalence of this molecular subtype in a national MPN cohort and demonstrates a distinct pattern of MPL mutations in dual driver MPN. This brief audit further underscores the molecular and clonal complexity of this subset of MPN patients.