The impact of age and number of mutations on the size of clonal hematopoiesis

Wang, Kai; Zhang, Wen; Yi, Li; Zhao, Ming; Li, Peng-Yu; Fu, Mei-Hong; Lin, Rong; Zhu, Yong-Mei; Li, Jian-Feng; Yang, Wei-Ping; Fang, Hai; Chen, Zhu; Cai, Wang-Wei; Ren, Rui-Bao

doi:10.1073/pnas.2319364121

Cited by 3 publications

References 48 publications

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Aging and comprehensive molecular profiling in acute myeloid leukemia

Li,

Cheng,

Lin

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Acute myeloid leukemia (AML) is an aging-related and heterogeneous hematopoietic malignancy. In this study, a total of 1,474 newly diagnosed AML patients with RNA sequencing data were enrolled, and targeted or whole exome sequencing data were obtained in 94% cases. The correlation of aging-related factors including age and clonal hematopoiesis (CH), gender, and genomic/transcriptomic profiles (gene fusions, genetic mutations, and gene expression networks or pathways) was systematically analyzed. Overall, AML patients aged 60 y and older showed an apparently dismal prognosis. Alongside age, the frequency of gene fusions defined in the World Health Organization classification decreased, while the positive rate of gene mutations, especially CH-related ones, increased. Additionally, the number of genetic mutations was higher in gene fusion–negative (GF-) patients than those with GF. Based on the status of CH- and myelodysplastic syndromes (MDS)-related mutations, three mutant subgroups were identified among the GF- AML cohort, namely, CH-AML, CH-MDS-AML, and other GF- AML. Notably, CH-MDS-AML demonstrated a predominance of elderly and male cases, cytopenia, and significantly adverse clinical outcomes. Besides, gene expression networks including HOXA / B , platelet factors, and inflammatory responses were most striking features associated with aging and poor prognosis in AML. Our work has thus unraveled the intricate regulatory circuitry of interactions among different age, gender, and molecular groups of AML.

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Aging and comprehensive molecular profiling in acute myeloid leukemia

Li,

Cheng,

Lin

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Risk of Incident Cytopenia in Clonal Hematopoiesis

Brogan,

Kishtagari,

Corty

et al. 2024

Preprint

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Clonal hematopoiesis of indeterminate potential (CHIP) is an asymptomatic condition associated with elevated risk for myeloid neoplasms (MN). Patients with CHIP and cytopenia are at greater risk of MN. Quantifying the incidence of cytopenia and identifying risk factors among CHIP patients is critical for improving clinical management. We analyzed sequencing data from 805,249 participants in the NIH All of Us Research Program (AoU), Vanderbilt's BioVU repository, and UK Biobank (UKB). Genetic mutations, laboratory values, and MN diagnoses were included in survival analyses to determine predictors of cytopenia in individuals with CHIP and matched controls. The cohort contained 9,374 CHIP cases and 24,749 controls. Cytopenia occurred in 13.5% of cases and 11.6% of controls (HR = 1.17, 95% confidence interval: 1.10 — 1.25, P=2.5 x 10−6). Cytopenia risk factors included smoking, male sex, variant allele frequency ≥ 0.20, age ≥ 65, mean corpuscular volume ≥ 100 femtoliters, red cell distribution width ≥ 15%, mutations in high-risk CHIP genes, and ≥ 2 CHIP mutations. In BioVU, 45% of participants with ≥ 4 risk factors progressed to cytopenia within two years. Individuals with CHIP and cytopenia progressed to MN at a rate of ~2% per year, compared to <0.1% per year for those without cytopenia. Longitudinal analysis across three cohorts demonstrated an increased risk of cytopenia in CHIP patients and identified those at highest risk. These findings suggest that cytopenia is a critical step in progression from CHIP to MN, underscoring its utility as an endpoint in cancer prevention trials for CHIP patients.

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Decoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights

Pendse,

Loeffler

2024

Cancers

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Clonal hematopoiesis (CH), the relative expansion of mutant clones, is derived from hematopoietic stem cells (HSCs) with acquired somatic or cytogenetic alterations that improve cellular fitness. Individuals with CH have a higher risk for hematological and non-hematological diseases, such as cardiovascular disease, and have an overall higher mortality rate. Originally thought to be restricted to a small fraction of elderly people, recent advances in single-cell sequencing and bioinformatics have revealed that CH with multiple expanded mutant clones is universal in the elderly population. Just a few years ago, phylogenetic reconstruction across the human lifespan and novel sensitive sequencing techniques showed that CH can start earlier in life, decades before it was thought possible. These studies also suggest that environmental factors acting through aberrant inflammation might be a common theme promoting clonal expansion and disease progression. However, numerous aspects of this phenomenon remain to be elucidated and the precise mechanisms, context-specific drivers, and pathways of clonal expansion remain to be established. Here, we review our current understanding of the cellular mechanisms driving CH and specifically focus on how pro-inflammatory factors affect normal and mutant HSC fates to promote clonal selection.

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The impact of age and number of mutations on the size of clonal hematopoiesis

Cited by 3 publications

References 48 publications

Aging and comprehensive molecular profiling in acute myeloid leukemia

Aging and comprehensive molecular profiling in acute myeloid leukemia

Risk of Incident Cytopenia in Clonal Hematopoiesis

Decoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights

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