Page 49 - 2020_08-Haematologica-web

Clonal hematopoiesis and platelet traits
Figure 1. Clonal hematopoiesis of indeterminate potential (CHIP)-related genes affecting platelet traits and the risk of thrombosis or bleeding. Mutations in genes associated with a thrombotic or bleeding risk are indicated in red and blue, respectively. For genes indicated in black, no such associations are known yet.
quent, can occur in patients with CMML, MDS or MPN.26 It is considered that DNMT3A mutations in hematopoietic stem cells lead to a pre-leukemic state, waiting for addi- tional mutations to induce leukemia. The time interval from first appearance of the mutation to disease is, how- ever, unclear.26
In agreement with its relevance for clonal hematopoiesis, a recent report points to an increased inci- dence of acquired DNMT3A mutations in the elderly, with a prevalence of about 15% at 60-69 years of age.1 Combined with a JAK2 V617F mutation (see below), the mutated DNMT3A gene associates with essential throm- bocythemia (ET) and polycythemia vera (PV).26 Current understanding is that first acquisition of a DNMT3A muta- tion followed by JAK2 will result in an ET phenotype. On the other hand, first appearance of the JAK2 mutation may result in a PV phenotype.26 Overall, DNMT3A mutations in AML patients are associated with higher platelet counts than patients with WT-DNMT3A; however, the absolute count is still low (<150x109/L).28
Regarding atherosclerosis development and atherothrombosis, studies report increased inflammation, linked to mutated DNMT3A, possibly due to a higher pro- duction of cytokines.29 Indeed, in patients carrying an acquired mutation of DNMT3A, the risk of CVD appears to be doubled.1 The higher platelet count observed in AML patients with DNMT3A mutations likely occurs sec- ondary to the pro-inflammatory phenotype. So far, no mechanism has been found to link DNMT3A mutations directly to platelet traits.
IDH2
The enzyme isocitrate dehydrogenase NADP+ 2 (IDH2)
localized in mitochondria generates NADPH from NADP+, whilst catalyzing the oxidative decarboxylation of isoci- trate, ultimately producing D-2-hydroxy-glutarate. By producing NADPH, IDH2 regulates the mitochondrial redox balance, hence mitigating cellular oxidative damage.30 As expected, genetic mutations in IDH2 are described to be associated with metabolic diseases. On the other hand, somatic mutations of IDH2 are found in several cancers, including hematologic malignancies, sar- comas and colon cancer. This is compatible with a role of IDH2 as epigenetic regulator, although the direct evidence for epigenetic effects is still indirect.
The most frequent clonal mutations in IDH2, identified in patients with de novo AML, concern the protein arginine residues R140Q and R172K. These variants cause a gain- of-function resulting in an abnormal, damaging produc- tion of D-2-hydroxyglutaric acid, leading to a hyperme- thylated state of DNA and histones.30 In comparison to non-carriers, AML patients carrying the somatic IDH2 mutations showed a higher platelet count, although the absolute platelet count was still low (<150x109/L).31 The same trend for platelet count has also been found in MDS patients.32 Next to this, in primary myelofibrosis, IDH mutations can form a risk factor for leukemic transforma- tion.33 No association with thrombotic events is known for these patient groups, but bleeding was more common in mutant-carrying patients. In the elderly, the percentage of individuals with clonal hemostasis driver mutations in IDH2 appeared to be rather low at around 1%.16 Together, this suggests only mild effects of somatic changes in this gene on clonal hematopoiesis, associated with a slight increase in platelet count by a so far unknown mechanism and an increased bleeding tendency.
haematologica | 2020; 105(8)
2025