Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

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.

The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

“…A share of TN MPNs discloses variants of myeloid neoplasm-/CHIP-associated genes (i.e., DNMT3A, TET2, and ASXL1) with ascertained or putative pathogenicity [58,71,72].…”

“…Overall, subsets of CHIP may thus represent precursor hematopoietic clones, characterized by normal blood cell counts and intrinsic potential to TN MPN evolution [55,72]. Further clinical-pathological and molecular studies are needed to test this fascinating possibility.…”

Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease

“…Such patients have a high risk of thrombosis and CVD. JAK2 is involved in erythropoietin and thrombopoietin pathways [101][102][103]. Mice receiving JAK2 mutant bone marrow transplant cells develop accelerated heart failure [104].…”

Clonal hematopoiesis by DNMT3A mutations as a common finding in idiopathic splanchnic vein thrombosis

“…The different VAF of these two mutations suggests the presence of compound heterozygosity or two distinct subclones, further highlighting the tendency to select for these aberrations in patients with SVT. While DNMT3A mutations are associated with MPN/myelodysplastic syndromes, 11 to our knowledge no data have linked DNMT3A mutations to thrombosis. Lastly, one patient had a mutation in enhancer of zeste homolog 2 ( EZH2 ), which is a histone-lysine N-methyltransferase enzyme.…”