Recent Advances in Molecular Diagnostics and Targeted Therapy of Myeloproliferative Neoplasms

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.

The Impact of JAK2 V617F, CALR, and MPL Mutations as Molecular Diagnostic Markers of Myeloproliferative Neoplasms in Kurdish Patients. A Single-center Experience

“…Based on studies, JAK2 V617F mutation was seen in 95% of PV patients and about 50-60% of ET and PMF patients (12,(17)(18)(19). In this study, it was shown that the frequency of JAK2 V617F mutation was 97.1% in PV patients, 50% in ET patients, and 60.25%in PMF patients.…”

“…Driver mutations in MPN are now formally included in the WHO diagnostic criteria for primary myelofibrosis (58 percent JAK2, 25 percent CALR and 7 percent MPL), PV (98 percent JAK2 mutational frequency), and ET (60 percent JAK2, 22 percent CALR, and 3 percent MPL mutational frequency) (10). Considering that there are genetic differences depending on the geography (11,12), and there is no study on the genetic mutation status of these diseases in the Iraqi region and especially Iraqi Kurdistan, this study aims to use molecular aspects for the diagnosis of MPN according to WHO criteria 2016 that (not only depend on morphological and clinical aspects for diagnosis) but using JAK2, CALR, MPL genes for diagnosis and prognosis.…”

Mutational Analysis of Driver and Non-driver Mutations of Philadelphia Chromosome-negative Myeloproliferative Neoplasms; Diagnosis and Recent Advances in Treatment

“…The standard treatment, particularly for PV, is therapeutic phlebotomy to achieve hematocrit <45%, sometimes combined with other therapies. Antiplatelet drugs such aspirin, and cytoreductive chemotherapy, such as, hydroxyurea (Hydrea®), α-interferon or anagrelide (Agrylin® ), are used instead of or in combination with phlebotomy for patients with a history of thrombosis to suppress the excess production of blood cells [65].…”

“…There is no single treatment option that can effectively treat all patients with MPN. The choice of treatment including the use of platelet-lowering agents, is based on risk factors including age, history of bleeding or thrombosis, vascular risk, severity of symptoms, and drug tolerance [65].…”

“…The discovery of the JAK2 V617F oncogene mutation contributed to the exploitation of the JAK2 tyrosine kinase as an important therapeutic target. Small-molecule inhibitors for JAK2 were developed for treatment of patients intolerant or refractory to hydroxyurea, particularly in patients with PV, and numerous drugs that inhibit JAK2 are currently in clinical trials [65,73].…”