Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms

SIMPLE SUMMARY: Myeloproliferative neoplasms (MPN) are clonal hematologic malignancies with dysregulated myeloid blood cell production driven by JAK2, calreticulin, and MPL gene mutations. Technological advances have revealed a heterogeneous genomic landscape with additional mutations mainly in epigenetic regulators and splicing factors, which are of diagnostic and prognostic value and may inform treatment decisions. Thus, genetic testing has become an integral part of the state-of-the-art work-up for MPN. The finding that JAK2, CALR, and MPL mutations activate JAK2 signaling has promoted the development of targeted JAK2 inhibitor therapies. However, their disease-modifying potential remains limited and investigations of additional molecular vulnerabilities in MPN are imperative to advance the development of new therapeutic options. Here, we summarize the current insights into the genetic basis of MPN, its use as diagnostic and prognostic tool in clinical settings, and recent advances in targeted therapies for MPN. ABSTRACT: Somatic mutations in JAK2, calreticulin, and MPL genes drive myeloproliferative neoplasms (MPN), and recent technological advances have revealed a heterogeneous genomic landscape with additional mutations in MPN. These mainly affect genes involved in epigenetic regulation and splicing and are of diagnostic and prognostic value, predicting the risk of progression and informing decisions on therapeutic management. Thus, genetic testing has become an integral part of the current state-of-the-art laboratory work-up for MPN patients and has been implemented in current guidelines for disease classification, tools for prognostic risk assessment, and recommendations for therapy. The finding that JAK2, CALR, and MPL driver mutations activate JAK2 signaling has provided a rational basis for the development of targeted JAK2 inhibitor therapies and has fueled their translation into clinical practice. However, the disease-modifying potential of JAK2 inhibitors remains limited and is further impeded by loss of therapeutic responses in a substantial proportion of patients over time. Therefore, the investigation of additional molecular vulnerabilities involved in MPN pathogenesis is imperative to advance the development of new therapeutic options. Combination of novel compounds with JAK2 inhibitors are of specific interest to enhance therapeutic efficacy of molecularly targeted treatment approaches. Here, we summarize the current insights into the genetic basis of MPN, its use as a diagnostic and prognostic tool in clinical settings, and the most recent advances in targeted therapies for MPN.