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Clonal hematopoiesis and platelet traits
extensive reorganization of cytoskeletal proteins is required for proplatelet formation and the budding of platelets.6
A number of recent studies stipulate that the incidence of cardiovascular disease (CVD), such as coronary artery disease, heart failure and ischemic stroke, is higher in patients with so-called somatic driver mutations in hematopoietic stem or progenitor cells, resulting in a clon- al expansion of a subpopulation of blood cells.1 This process, referred to as clonal hematopoiesis of indetermi- nate potential (CHIP), was proposed to define individuals with somatic clonal mutations in genes related to hemato- logic malignancies with variant allele fractions of >2%, but without a known hematologic malignancy or other clonal disorder.7 This premalignant state is considered to be relatively frequent in the elderly population, where somatic mutations accumulate in a variety of genes con- trolling hematopoietic stem cell maintenance, expansion and survival. Although CHIP increases the risk of develop- ing hematologic cancer, mostly myeloid neoplasms, the absolute risk is still small. Several excellent recent reviews describe in detail the etiology of clonal hematopoiesis and its relation with CVD.1,8,9 So far, attention has mainly been focused on proposed mechanisms of accelerated inflam- mation-driven atherosclerosis and increased thrombosis risk through altered function of innate immune cells.
In the present paper, we took a different approach. We confined our search to the current evidence on CHIP muta- tions that are directly or indirectly linked to qualitative or quantitative platelet traits. Starting from the Online Mendelian Inheritance in Man (OMIM) database comple- mented with recent literature, we selected and discussed genes that were linked to clonal hematopoiesis as well as to the platelet traits count and function. Since CHIP mutations appeared not to be only associated with increased platelet count and/or function, but also with decreases in these platelet traits, its potential relation to both (athero)throm- botic and hemostatic disorders is presented in this review.
Section 1: Clonal mutations in genes associated with increased platelet count and/or function
For several genes encoding for transcription regulators (ASXL1), epigenetic regulators (DNMT3A, IDH2) and cell signaling proteins (ABL1, BCR, BRAF, JAK2, SH2B3), clon- al mutations are known that enhance platelet production, which can be accompanied by enhanced platelet function- ality. Related effects are described for several genes with divergent roles (ABCB6, SF3B1) (Table 1 and Figure 1).
ABCB6
Multiple so-called ABC transporters play a role in lipid trafficking, and thus may contribute to atherosclerosis. However, the ABCB6 gene product (ATP binding cassette subfamily B member 6) facilitates the ATP-dependent import of porphyrins and heme into mitochondria.10 Markedly, germline mutations of ABCB6 are associated with several disease phenotypes, including dyschromatosis, microph- thalmia and pseudo-hyperkalemia.
The gene ABCB6 is highly expressed in BM megakary- ocyte progenitor cells and megakaryocytes, but only mod- erately in platelets. Evidence regarding CVD mainly comes from animal studies. In mice, deficiency in Abcb6
increased megakaryopoiesis and thrombopoiesis, result- ing in an increased platelet count and larger platelet vol- ume, effects that were explained by higher oxidative stress in the presence of accumulating porphyrins.11 The platelets produced in these mice were hyper-reactive and furthermore, against a high-lipid background, attracted leukocytes, thus enhancing atherosclerosis.10,11
In patients with acute promyelocytic or myeloid leukemia, RNA expression levels of ABCB6 are reduced, suggesting the occurrence of also acquired clonal muta- tions in this gene.12 However, so far no strong association with CHIP has been found.8
ASXL1
The transcriptional regulator Additional sex combs like 1 (ASXL1) is a chromatin-binding protein, which acts as tumor suppressor and is implicated in the maintenance of normal hematopoiesis. Somatic mutations of this gene are found in patients with a variety of myeloid malignancies, including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), myelodysplastic syn- drome (MDS), and myeloproliferative neoplasm (MPN).13 In particular, mutations in ASXL1 are detected in 10% of MDS patients and 40% of CMML patients.14 Hence, this gene is considered as a driver of leukemia and myelodysplasia. The majority of (somatic) mutations provoke a truncation of the C-terminus of the protein, resulting in a loss of transcription regulation. In addition, the truncated form can interact with other proteins to modulate cell proliferation.15 In mouse models, transgenic expression of a C-terminal truncated Asxl1 mutant resulted in age-dependent anemia, thrombo- cytosis, and morphological dysplasia.13 A similar type of thrombocytosis is seen in MDS-refractory anemia patients, carrying ASXL1 mutations.13 The prevalence of acquired hematopoietic mutations in ASXL1 in a healthy population of 60-69 years of age was estimated at 1.5%, and was asso- ciated with twice the risk of developing CVD.16
BCR and ABL1
The somatic gene effects of Breakpoint cluster region pro-
tein (BCR) and Abelson murine leukemia viral oncogene homolog 1 (ABL1) are highly related, if only because the two proteins share signaling pathways. The proto-onco- gene ABL1 contains an auto-inhibitory SH3 domain which, when deleted, turns it into an oncogene. During a somatic reciprocal translocation of chromosomes 22 and 9, both genes can fuse together. The encoded BCR-ABL1 fusion protein is frequently detected in patients with chronic myeloid leukemia (CML) (90%) or acute lym- phoblastic leukemia (ALL) (30%).17 While CML patients mostly carry the 210 amino-acid variant of BCR-ABL, in ALL patients also a shorter 185 amino-acid variant is pres- ent. Both fusion forms display constitutive protein tyro- sine kinase activity.17
The current understanding is that aberrant roles of BCR and ABL1 in hematopoiesis are a consequence of fusion formation, although the main evidence comes from case studies. A fusion variant has been described, which is associated with an increased platelet count, although the mechanism is still unclear.18 In the few healthy adults car- rying a BCR-ABL1 fusion mutation hematopoietic malig- nancies were not detected. On the other hand, BCR-ABL1 fusions can be considered as indicators for a premalignant state, while the absolute risk of developing CVD is smaller than for the JAK2 V617F mutation.19
haematologica | 2020; 105(8)
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