Clonal Hematopoiesis and JAK2V617F Mutations in Patients With Cardiovascular Disease

Yokokawa, Tetsuro; Misaka, Tomofumi; Kimishima, Yusuke; Wada, Kento; Minakawa, Keiji; Kaneshiro, Takashi; Yoshihisa, Akiomi; Ikeda, Kazuhiko; Takeishi, Yasuchika

doi:10.1016/j.jaccao.2021.01.001

Cited by 14 publications

(14 citation statements)

References 5 publications

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“…(3) Vascular endothelial cell expression of JAK2 V617F promotes a prothrombotic state due to increased P‐selectin expression 16 . Recently, clonal hematopoiesis (CH) has been identified and genetic mutations associated with the disease have been detected before the development of hematological malignancies 17,18 . In addition, when CH occurs and the variant allele frequency (VAF) exceeds 2%, it is called CH with indeterminate potential (CHIP) 17 .…”

Section: Discussionmentioning

confidence: 99%

“… 16 Recently, clonal hematopoiesis (CH) has been identified and genetic mutations associated with the disease have been detected before the development of hematological malignancies. 17 , 18 In addition, when CH occurs and the variant allele frequency (VAF) exceeds 2%, it is called CH with indeterminate potential (CHIP). 17 JAK2 V617F‐CHIP holders had a higher incidence of both arterial and venous thromboses than non‐holders.…”

Section: Discussionmentioning

confidence: 99%

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Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation

Yasuda,

Chiba,

Nishitani

et al. 2024

Clinical Case Reports

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Key Clinical MessageHematopoietic neoplasms can cause adrenal infarction. In cases of thrombosis occurring at uncommon sites, it is necessary to consider evaluating for the JAK2V617F mutation, even in the absence of notable abnormalities in blood counts.AbstractAdrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46‐year‐old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm‐unclassifiable, featuring a JAK2V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms. We should consider evaluating for JAK2V617F mutation even in cases of thrombosis at unusual sites, including adrenal infarction, even if there are no considerable abnormalities in blood counts.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation

Yasuda,

Chiba,

Nishitani

et al. 2024

Clinical Case Reports

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“…Furthermore, a relatively large clone size with a VAF > 10% was needed to impose the cardiovascular risk [ 42 ]. The distinct effect of JAK2 V617F on the cardiovascular risk was confirmed in a Japanese cohort studying MPN driver mutations [ 41 ]. In line, the presence of CHIP in individuals with unexplained erythrocytosis but not meeting the diagnostic criteria of MPN has been associated with an increased cardiovascular morbidity and mortality [ 57 ].…”

Section: Chip and Cardiovascular Diseasementioning

confidence: 94%

“…On the other hand, phylogenetic studies of clonal development have recently shown that the acquisition of JAK2 V617F precedes the phenotypic diagnosis of MPN by 30 years on average with very slow expansion of the mutated clone over decades [ 40 ]. While these findings argue for a more differentiated consideration of JAK2 V617F as diagnostic criterion for MPN (e.g., via a minimal required VAF), the cardiovascular risk—which is also a hallmark of JAK2 -mutated MPN—is substantial in JAK2 -mutated patients even if the diagnostic criteria for MPN are not met [ 41 , 42 ]. The diagnostic significance of CHIP-mutations in the context of polycythemia, thrombocythemia, and/or leukocytosis is not limited to the classical hotspot mutations in JAK2 , MPL , or CALR as mutations in other genes are recurrently found in so called triple-negative MPN [ 43 ].…”

Section: Chip and Hematologic Neoplasmsmentioning

confidence: 99%

Clinical Significance of Clonal Hematopoiesis of Indeterminate Potential in Hematology and Cardiovascular Disease

Hoermann

2022

Diagnostics

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Liquid profiling uses circulating tumor DNA (ctDNA) for minimal invasive tumor mutational profiling from peripheral blood. The presence of somatic mutations in peripheral blood cells without further evidence of a hematologic neoplasm defines clonal hematopoiesis of indeterminate potential (CHIP). CHIP-mutations can be found in the cell-free DNA (cfDNA) of plasma, are a potential cause of false positive results in liquid profiling, and thus limit its usage in screening settings. Various strategies are in place to mitigate the effect of CHIP on the performance of ctDNA assays, but the detection of CHIP also represents a clinically significant incidental finding. The sequelae of CHIP comprise the risk of progression to a hematologic neoplasm including therapy-related myeloid neoplasms. While the hematological risk increases with the co-occurrence of unexplained blood count abnormalities, a number of non-hematologic diseases have independently been associated with CHIP. In particular, CHIP represents a major risk factor for cardiovascular disease such as atherosclerosis or heart failure. The management of CHIP requires an interdisciplinary setting and represents a new topic in the field of cardio-oncology. In the future, the information on CHIP may be taken into account for personalized therapy of cancer patients.

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“…While it seems intuitive that CH is associated with an increased risk of leukemia (8,(15)(16)(17)(18)(19)(20)(21), growing evidence shows that it is also linked to multiple disease conditions outside of the hematopoietic system, and increased overall mortality (9,(22)(23)(24)(25)(26). This includes cardiovascular disease (CVD) (23,(27)(28)(29), infections (30), ulcerative colitis (31), and a wide spectrum of solid tumors (27,(32)(33)(34)(35)(36)(37)(38)(39). In patients with solid tumors, the prevalence of CH similarly increases with age yet is notably more frequent (~30% of cases) and correlates with shorter survival due primarily to solid tumor progression (1,34,40).…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic-specific heterozygous loss ofDnmt3aexacerbates colitis-associated colon cancer

Feng

Newsome

Robinson

et al. 2022

Preprint

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Clonal hematopoiesis (CH) is defined as clonal expansion of mutant hematopoietic stem cells absent diagnosis of a hematologic malignancy. Presence of CH in solid tumor patients, including colon cancer, correlates with shorter survival. We hypothesized that bone marrow-derived cells with heterozygous loss-of-function mutations of DNMT3A, the most common genetic alteration in CH, contribute to the pathogenesis of colon cancer. In a mouse model that combines colitis-associated colon cancer with experimental CH driven by Dnmt3a(+/del), we found higher tumor penetrance and increased tumor burden compared to controls. Histopathological analysis revealed accentuated colonic epithelium injury, dysplasia and adenocarcinoma formation. Transcriptome profiling of colon tumors identified enrichment of gene signatures associated with carcinogenesis, including angiogenesis. Treatment with the angiogenesis inhibitor axitinib eliminated the colon tumor-promoting effect of experimental CH driven by Dnmt3a haploinsufficiency. This study provides conceptually novel insights into non-tumor-cell-autonomous effect of hematopoietic alterations on colon carcinogenesis and identifies potential therapeutic strategies.

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Clonal Hematopoiesis and JAK2V617F Mutations in Patients With Cardiovascular Disease

Cited by 14 publications

References 5 publications

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2V617F mutation

Clinical Significance of Clonal Hematopoiesis of Indeterminate Potential in Hematology and Cardiovascular Disease

Hematopoietic-specific heterozygous loss ofDnmt3aexacerbates colitis-associated colon cancer

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