Abstract
Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.
Highlights
Molecular diagnosis of myeloproliferative neoplasms (MPNs) have provided groundbreaking knowledge of their biology and genetic landscape but revolutionized the speed and accuracy of diagnosis
The earliest discovery of genetic aberrations associated with hematological malignancy was the (9;22) translocation or Philadelphia chromosome, resulting in a fusion between the genes coding for BCR and ABL1, identifying patients with chronic myelogenous leukemia (CML)
The gene dosage of these mutations is strongly associated with the disease subtype, but it is far unclear why the homozygous clones that are present in essential thrombocythemia (ET) patients do not outcompete the heterozygous clones as seen in polycythemia vera (PV) patients
Summary
Molecular diagnosis of myeloproliferative neoplasms (MPNs) have provided groundbreaking knowledge of their biology and genetic landscape but revolutionized the speed and accuracy of diagnosis. The earliest discovery of genetic aberrations associated with hematological malignancy was the (9;22) translocation or Philadelphia chromosome, resulting in a fusion between the genes coding for BCR and ABL1, identifying patients with chronic myelogenous leukemia (CML). The MPNs are considered to be initiated when changes in the genetic landscape of an HSC leads to clonal expansion and result in the generation of a malignant clone [6]. CH with a relatively low risk of progression to neoplasms is not a harmless condition but leads to decreased patient survival independent of hematological malignancies, increased risk of coronary heart disease, earlier onset of myocardial infarction, and is considered a cardiovascular risk factor [11,18,19,20,21]. I will discuss the role of driver mutations for the detection of small hematopoietic clones that may lead to malignancy or cardiovascular disease (CVD)
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