2022
DOI: 10.1001/jamacardio.2022.0386
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TET2-Driven Clonal Hematopoiesis and Response to Canakinumab

Abstract: IMPORTANCE Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1β signaling.OBJECTIVE To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1β neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS). DESIGN… Show more

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Cited by 147 publications
(100 citation statements)
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References 31 publications
(95 reference statements)
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“…This process is also associated with risk for coronary disease, causing investigators to revisit the clonal hypothesis of atherosclerosis and its overlap with the clonally-expanding cancer stem cell. While the precise molecular mechanism linking CHIP mutations to heart disease remains undefined, inflammasome activation is thought to be central to this process (46-49). Interestingly, patients in the CANTOS trial with CHIP mutations benefited more from canakinumab than those without a CHIP mutation (49).…”
Section: Discussionmentioning
confidence: 99%
“…This process is also associated with risk for coronary disease, causing investigators to revisit the clonal hypothesis of atherosclerosis and its overlap with the clonally-expanding cancer stem cell. While the precise molecular mechanism linking CHIP mutations to heart disease remains undefined, inflammasome activation is thought to be central to this process (46-49). Interestingly, patients in the CANTOS trial with CHIP mutations benefited more from canakinumab than those without a CHIP mutation (49).…”
Section: Discussionmentioning
confidence: 99%
“…This analysis had insufficient power to assess the effect of IL-1β neutralization in those participants with JAK2 mutations. 175 Anti-inflammatory therapies thus merit further exploration in the treatment of MPN and cancer in general. 71 , 174 , 176 …”
Section: Potential Novel Cardiovascular Therapeutic Targets In Patien...mentioning
confidence: 99%
“…30 Consistently, in an exploratory preliminary analysis, patients with a TET2 mutant have an improved response to canakinumab (hazard ratio [HR] = 0.38) relative to the response to overall response to canakinumab (HR = 0.93) in the CANTOS trial. 37 In addition to the pharmacological evidence, human genetic studies provide more support for a causal role of inflammation in CVD. IL-6 can be a downstream product of IL-1β signaling and increased IL-6 production and activity are considered to be a common mediator in chronic inflammation associated with CVD.…”
Section: Chip and Cardiovascular Diseasementioning
confidence: 99%