Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN

Blood, Journal Year: 2022, Volume and Issue: 140(12), P. 1345 - 1377

Published: July 7, 2022

Abstract The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis management acute myeloid leukemia (AML) in adults are widely recognized among physicians investigators. There have been major advances our understanding AML, including new knowledge about molecular pathogenesis leading to an update disease classification, technological progress genomic diagnostics assessment measurable residual disease, successful development therapeutic agents, such as FLT3, IDH1, IDH2, BCL2 inhibitors. These prompted this that includes a revised ELN genetic risk response criteria, treatment recommendations.

Language: Английский

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A compendium of mutational cancer driver genes

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(10), P. 555 - 572

Published: Aug. 10, 2020

Language: Английский

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Somatic mutation rates scale with lifespan across mammals

Nature, Journal Year: 2022, Volume and Issue: 604(7906), P. 517 - 524

Published: April 13, 2022

Abstract The rates and patterns of somatic mutation in normal tissues are largely unknown outside humans 1–7 . Comparative analyses can shed light on the diversity mutagenesis across species, long-standing hypotheses about evolution their role cancer ageing. Here we performed whole-genome sequencing 208 intestinal crypts from 56 individuals to study landscape 16 mammalian species. We found that was dominated by seemingly endogenous mutational processes all including 5-methylcytosine deamination oxidative damage. With some differences, signatures other species resembled those described 8 , although relative contribution each signature varied Notably, rate per year greatly exhibited a strong inverse relationship with lifespan, no life-history trait studied showing comparable association. Despite widely different life histories among examined—including variation around 30-fold lifespan 40,000-fold body mass—the burden at end only factor 3. These data unveil common mammals, suggest evolutionarily constrained may be contributing

Language: Английский

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Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives

Frontiers in Genetics, Journal Year: 2021, Volume and Issue: 11

Published: Jan. 21, 2021

Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate telomere attrition also common feature age-related diseases. Therefore, length (TL) has been recognized for long time as one the best biomarkers Recent research findings, however, indicate that TL per se can only allow rough estimate aging hardly be regarded clinically important risk marker pathologies mortality. Evidence obtained other indicators such certain immune parameters, indices epigenetic age, etc., could stronger predictors health status chronic disease. However, despite these issues limitations, remains to very informative in accessing biological age when used along with markers homeostatic dysregulation, frailty index, clock, etc. This review article aimed at describing current state art field discussing recent findings divergent viewpoints regarding usefulness leukocyte estimating human age.

Language: Английский

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Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6

Nature Reviews Cardiology, Journal Year: 2020, Volume and Issue: 18(1), P. 58 - 68

Published: Sept. 11, 2020

Language: Английский

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The longitudinal dynamics and natural history of clonal haematopoiesis

Nature, Journal Year: 2022, Volume and Issue: 606(7913), P. 335 - 342

Published: June 1, 2022

Abstract Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where phenomenon is termed clonal haematopoiesis 1–4 . The understanding of how and when develops, factors that govern its behaviour, it interacts ageing these variables relate to malignant progression remains limited 5,6 Here we track 697 clones from 385 individuals 55 years age or older over a median 13 years. We find 92.4% expanded at stable exponential rate study period, different driving substantially growth rates, ranging 5% ( DNMT3A TP53 ) more than 50% per year SRSF2 P95H ). Growth rates same mutation differed approximately ±5% year, proportionately affecting slow drivers substantially. By combining our time-series data phylogenetic analysis 1,731 whole-genome sequences colonies 7 an group, reveal distinct patterns lifelong behaviour. -mutant preferentially early life displayed slower old context increasingly competitive oligoclonal landscape. contrast, splicing gene drove expansion only later life, whereas TET2 emerged all ages. Finally, show faster carry higher risk progression. Our findings characterize natural history give fundamental insights into interactions between mutation, selection.

Language: Английский

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The landscape of aging

Science China Life Sciences, Journal Year: 2022, Volume and Issue: 65(12), P. 2354 - 2454

Published: Sept. 2, 2022

Language: Английский

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TET2-Driven Clonal Hematopoiesis and Response to Canakinumab

JAMA Cardiology, Journal Year: 2022, Volume and Issue: 7(5), P. 521 - 521

Published: April 6, 2022

Importance

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related toTet2loss function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1β signaling.

Objective

To assess whether individuals have greater event reduction response to IL-1β neutralization the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS).

Design, Setting, Participants

This randomized clinical trial took place from April 2011 June 2017 at more than 1000 sites 39 countries. Targeted deep sequencing genes previously a subset participants using genomic DNA prepared baseline peripheral blood samples were analyzed. All had prior myocardial infarction elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis between December 2021.

Interventions

Canakinumab, an anti–IL-1β antibody, given doses 50, 150, 300 mg once every 3 months.

Main Measures

Major adverse events (MACE).

Results

A total 338 patients (8.6%) identified this evidence for clonal hematopoiesis. As expected, incidence age; mean (SD) age was 66.3 (9.2) years 61.5 (9.6) without CHIP. Unlike other populations not preselected protein, CANTOS population variants inTET2were common thanDNMT3A(119 103 vs 86 85 patients). Placebo-treated showed nonsignificant increase rate MACE compared Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04];P = .21). Exploratory analyses placebo-treated somatic variant eitherTET2orDNMT3A(n 58) equivocal 1.65 0.97-2.80];P .06). Patients due inTET2also reduced while taking canakinumab 0.38 0.15-0.96]) difference others (Pfor interaction .14).

Conclusions Relevance

These results are consistent observations raise possibility those withTET2variants may respond better Future studies required further substantiate hypothesis.

Trial Registration

ClinicalTrials.gov Identifier:NCT01327846

Language: Английский

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Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(8), P. 1155 - 1166

Published: July 14, 2022

Abstract Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over third people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map landscape inherited predisposition CH, increasing number germline associations with CH in European-ancestry populations 4 14. Genes at new loci implicate DNA damage repair ( PARP1 , ATM CHEK2 ), hematopoietic migration/homing CD164 ) myeloid oncogenesis SETBP1 ). Several were CH-subtype-specific including variants TCL1A that had opposite DNMT3A - versus TET2 -mutant two most common subtypes, proposing key roles for these development. Mendelian randomization analyses showed smoking longer leukocyte telomere length are causal risk factors increases risks myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation epigenetic ageing.

Language: Английский

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Ageing and rejuvenation of tissue stem cells and their niches

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(1), P. 45 - 62

Published: July 20, 2022

Language: Английский

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