Chronic myeloproliferative neoplasms (MPNs) represent a group of clonal hematopoietic stem cell disorders characterized by uncontrolled proliferation of one or more myeloid lineages. The discovery of recurrent driver mutations has transformed the diagnostic, prognostic, and therapeutic landscape of these disorders. This article reviews the clinical relevance of genetic testing in MPNs, with a focus on driver and additional mutations, and their implications for patient management.

Chronic myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are defined by clonal proliferation of hematopoietic progenitors. The molecular era has revealed the critical role of somatic mutations in their pathogenesis. Genetic testing has now become integral to diagnosis, risk stratification, and therapeutic decision-making.

Driver Mutations

JAK2

- JAK2 V617F mutation is present in approximately 95% of PV cases and 50–60% of ET and PMF cases.

- It leads to constitutive activation of the JAK-STAT signaling pathway, driving cytokine-independent proliferation.

- Allele burden correlates with clinical phenotype and thrombotic risk.

CALR

- Detected in 20–30% of ET and PMF patients who are JAK2-negative.

- Mutations, mostly frameshift in exon 9, generate novel C-terminal peptides.

- CALR-mutated ET patients often present at a younger age, with higher platelet counts and relatively favorable prognosis.

MPL

- Mutations in the thrombopoietin receptor gene, most commonly W515L/K, occur in 3–5% of ET and PMF cases.

- They lead to constitutive activation of thrombopoietin signaling and megakaryocyte proliferation.

Additional Mutations

- Genes such as ASXL1, EZH2, SRSF2, IDH1/2, and TP53 are frequently mutated, particularly in PMF.

- These mutations are not disease-defining but provide prognostic information.

- ASXL1 mutation, for instance, is associated with adverse prognosis and impacts decisions regarding allogeneic stem cell transplantation.

Clinical Applications

Diagnosis

- The WHO (2022) and ICC (2022) classifications incorporate genetic testing into diagnostic criteria.

- Identification of JAK2, CALR, or MPL mutations confirms clonality and assists in differentiating MPNs from reactive conditions.

- Triple-negative patients (negative for JAK2, CALR, MPL) often exhibit more aggressive clinical behavior.

Prognosis

- Prognostic scoring systems such as MIPSS70, GIPSS, and DIPSS-plus include molecular findings.

- The presence of high-risk mutations predicts increased risk of progression to acute leukemia and reduced overall survival.

Therapeutic Implications

- JAK2 allele burden informs thrombotic risk stratification and the need for cytoreductive therapy.

- The detection of adverse mutations influences consideration for hematopoietic stem cell transplantation.

- Targeted therapies, such as JAK inhibitors, have been developed based on the molecular pathogenesis of MPNs.

Future Perspectives

The integration of next-generation sequencing (NGS) panels into clinical practice allows for comprehensive molecular profiling. This facilitates the development of personalized treatment strategies, including targeted therapies beyond JAK inhibition. Ongoing clinical trials are exploring agents directed against epigenetic regulators and splicing factors.

Genetic testing has revolutionized the approach to chronic myeloproliferative neoplasms. Driver mutations (JAK2, CALR, MPL) remain essential for diagnosis, while additional mutations provide prognostic and therapeutic guidance. The expanding role of molecular testing paves the way toward precision medicine in MPNs.