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• Identification of TP53 pathogenic variants at lower-than-expected variant allele frequencies (VAF) for Li Fraumeni Syndrome (LFS) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH). • Constitutional mosaic LFS and clonal hematopoiesis (CH) represent completely different entities with regards to cancer risk, family implications and management. • In a cancer genetics specialty clinic, approximately 17 % of TP53 genetic testing results were "mosaic". • Ancillary tissue testing can help confirm a diagnosis of mosaic LFS. • Half of mosaic TP53 results may be postzygotic mosaicism (PZM) and half clonal hematopoiesis (CH). Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management. Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of "mosaic". A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative. Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up. [Display omitted] [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with a range of adverse clinical outcomes. Accumulating evidence points to inflammatory processes resulting from innate immune responses as a cornerstone in AF pathogenesis. Genetic and epigenetic factors affecting leukocytes have been identified as key modulators of the inflammatory response. Inherited variants in genes encoding proteins involved in the innate immune response have been associated with increased risk for AF recurrence and stroke in AF patients. Furthermore, acquired somatic mutations associated with clonal hematopoiesis of indeterminate potential, leukocyte telomere shortening, and epigenetic age acceleration contribute to increased AF risk. In individuals carrying clonal hematopoiesis of indeterminate potential, myocardial monocyte-derived macrophage shift toward a proinflammatory phenotype may precipitate AF. Further studies are needed to better understand the role of genetic regulation of the native immune response in atrial arrhythmogenesis and its therapeutic potential as a target for personalized medicine. [Display omitted] • Inflammation plays a fundamental role in the pathogenesis of AF. • Genetic and epigenetic factors modulate inflammatory responses, and genetic variants influence the risk of developing AF. • Better understanding of the role of genetic variants affecting AF could enhance identification and individualized management of patients at risk. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cells are an emerging therapy for refractory lymphomas. Clonal hematopoiesis (CH), the preferential outgrowth of mutated bone marrow progenitors, is enriched in lymphoma patients receiving CAR-T cells. CAR-T therapy requires conditioning chemotherapy and often induces systemic inflammatory reactions, both of which have been shown to promote expansion of CH clones. Thus, we hypothesized that pre-existing CH clones could expand during CAR-T cell treatment. We measured CH at 154 timepoints longitudinally sampled from 26 patients receiving CD30.CAR-T therapy for CD30+ lymphomas on an investigational protocol (NCT02917083). Pre-treatment CH was present in 54% of individuals and did not correlate with survival outcomes or inflammatory toxicities. Longitudinal tracking of single clones in individual patients revealed distinct clone growth dynamics. Initially small clones, defined as VAF <1%, expanded following CAR-T administration, compared with relatively muted expansions of larger clones (3.37-fold vs. 1.20-fold, P = 0.0014). Matched clones were present at low magnitude in the infused CD30.CAR-T product for all CH cases but did not affect the product's immunophenotype or transduction efficiency. As cellular immunotherapies expand to become frontline treatments for hematological malignancies, our data indicates CAR-T recipients could be enriched for CH, and further longitudinal studies centered on CH complications in this population are warranted. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) is associated with elevated pro-inflammatory cytokines which act as a driving force for clonal expansion. Recurrent or chronic infections and sterile inflammation may predispose to CH, particularly in cases of germline predisposition. Blocking inflammation may be a viable therapeutic approach for high-risk CH and associated hematopoietic and non-hematopoietic health sequelae. Acquired genetic or cytogenetic alterations in a blood stem cell that confer clonal fitness promote its relative expansion leading to clonal hematopoiesis (CH). Despite a largely intact hematopoietic output, CH is associated with a heightened risk of progression to hematologic malignancies and with non-hematologic health manifestations, including cardiovascular disease and overall mortality. We focus on the evidence for the role of inflammation in establishing, maintaining and reciprocally being affected by CH. We describe the known pro-inflammatory signals associated with CH and preclinical studies that elucidated the cellular mechanisms involved. We review the evolving literature on early-onset CH in germline predisposition conditions and the possible role of immune dysregulation in this context. [ABSTRACT FROM AUTHOR]

De novo somatic mutations are difficult to analyze because of their random nature. Apart from the few clonally amplified mutations, the far majority differs from cell to cell. Recent advances in single-cell, single-molecule and high-depth sequencing have shown that somatic mutations accumulate with age in virtually all tissues. Mutations arise through errors during replication or repair of damaged DNA. Age-related somatic mutation accumulation is inevitable due to the lack of an evolutionary advantage in protecting genome sequence integrity far beyond the period of first reproduction. Somatic mutation rate might be mitigated by adopting genome maintenance strategies of (i) extremely long-lived animals; (ii) species living under high genotoxic conditions; or (iii) stem or germ cells. Genomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized repair mechanisms in somatic cells only to allow transmitting genetic information to the next generation, not to maximize sequence integrity long beyond the reproductive age. Recent studies have confirmed that somatic mutations, due to errors during genome repair and replication, accumulate in tissues and organs of humans and model organisms. Here, we describe recent advances in the quantitative analysis of somatic mutations in vivo. We also review evidence for or against a possible causal role of somatic mutations in aging. Finally, we discuss options to prevent, delay or eliminate de novo , random somatic mutations as a cause of aging. [ABSTRACT FROM AUTHOR]

On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype. The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery. Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes. The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64+CD14+CD16− circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium. HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte–derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165) [Display omitted] [ABSTRACT FROM AUTHOR]

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• Age-related clonal hematopoiesis is common in humans. • JAK2 V617F is one of the most relevant gene mutations in clonal hematopoiesis. • Clonal hematopoiesis with JAK2 V617F is associated with cardiovascular diseases. • Identification of JAK2 V617F-indivisuals is an approach to stratify the event risk. • JAK2 V617F-clonal hematopoiesis is a therapeutic target for cardiovascular diseases. Bone marrow-derived hematopoietic and immune cells play important roles in the onset and progression of cardiovascular diseases. Recent genetic analyses have discovered that clonal expansion of bone marrow hematopoietic stem/progenitor cells carrying somatic gene mutations is common and is increasing with age in healthy individuals who do not show any hematologic disorders, termed as clonal hematopoiesis. It is emergingly recognized that clonal hematopoiesis is a significant risk factor for cardiovascular diseases rather than a cumulative incidence risk of blood cancers. JAK2 V617F, a gain-of-function mutation, has been identified as one of the most important mutations in clonal hematopoiesis as well as the most frequent driver mutation in myeloproliferative neoplasms. Hematopoietic cell clones harboring JAK2V617F are causally associated with the pathogenesis of cardiovascular diseases. Here, we will review the key of JAK2 V617F-mediated clonal hematopoiesis including identification, prevalence, and biological impacts, linking to cardiovascular diseases and the related mechanisms. Clonal hematopoiesis with JAK2 V617F may be a novel therapeutic target for cardiovascular diseases, connected to precision medicines by detecting its presence. [Display omitted] [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with cardiovascular diseases and other disorders, possibly via inflammation. Recent research suggests a connection of CHIP with neurodegenerative disorders. We aimed to investigate the association between multiple system atrophy (MSA) and CHIP. We included 100 patients with MSA and 4457 controls. Targeted sequencing of peripheral blood DNA samples was performed, focusing on a panel of 25 genes commonly. The prevalence of CHIP in patients with MSA was assessed against controls at variant allele frequency (VAF) thresholds of 1.5 % and 2.0 %. DNMT3A mutation rates were significantly higher in patients with MSA, with a VAF of 1.5 %, which remained significant after adjusting for age and sex (adjusted odds ratio, 1.848; 95 % CI, 1.024–3.335; p = 0.0416). Our results suggest an association between DNMT3A mutations and MSA. • This study aimed to investigate the potential link between MSA and clonal hematopoiesis of indeterminate potential (CHIP). • The prevalence of CHIP in patients with MSA was assessed against controls at two variant allele frequency (VAF) thresholds. • DNMT3A mutation were higher in patients with MSA, with a VAF of 1.5 %, indicating a potential connection between MSA and CHIP. [ABSTRACT FROM AUTHOR]

Much has been learned about the genes and pathways that contribute to a diverse array of hematopoietic malignancies and other hematopoietic diseases. However, for many of these diseases, an allogeneic hematopoietic stem cell (HSC) transplant remains the preferred treatment option. This opinion article provides the perspective of a molecular immunologist who became a transplant patient after many years studying basic mechanisms of blood cell development. Among many lessons learned were the magnitude of racial and ethnic disparities in donor registries, the substantial improvement in outcomes over time that were due to the collective impact of numerous advances, the benefits and limitations of genetic and clinical data, and the remarkably intricate balance between promoting graft-versus-disease activity of donor cells while suppressing graft-versus-host disease (GVHD). Allogeneic hematopoietic stem cell (HSC) transplants are frequently the preferred treatment option for a broad range of hematopoietic malignancies and other hematopoietic disorders. International HSC donor registries allow patients to find human leukocyte antigen (HLA)-matched donors, but substantial racial and ethnic disparities exist that must be addressed. Allogeneic transplant outcomes have improved dramatically due to the collective impact of numerous improvements in pretransplant conditioning and post-transplant support. Histological, cytogenetic, and genetic data allow hematopoietic disorders to be classified and sometimes provide useful information about treatment options, but are often less informative than hoped. A major challenge after an HSC transplant is to strike an appropriate balance for each hematopoietic malignancy patient between suppressing graft-versus-host disease while promoting the elimination of residual diseased cells by the graft-versus-disease activity of donor cells. [ABSTRACT FROM AUTHOR]

Superficial plaque erosion causes many acute coronary syndromes. However, mechanisms of plaque erosion remain poorly understood, and we lack directed therapeutics for thrombotic complication. Human eroded plaques can harbor neutrophil extracellular traps (NETs) that propagate endothelial damage at experimental arterial lesions that recapitulate superficial erosion. Clonal Hematopoiesis of Indeterminate Potential (CHIP) denotes age-related clonal expansion of bone marrow-derived cells harboring somatic mutations in the absence of overt hematological disease. CHIP heightens the risk of cardiovascular disease, with the greatest increase seen in individuals with JAK2 V617F. Neutrophils from mice and humans with JAK2 V617F undergo NETosis more readily than Jak2 WT (wild-type) cells. We hypothesized that JAK2 V617F, by increasing propensity to NETosis, exacerbates aspects of superficial erosion. We generated Jak2 V617F and Jak2 WT mice with heterozygous Jak2 V617F in myeloid cells. We induced areas of denuded endothelium that recapitulate features of superficial erosion and assessed endothelial integrity, cellular composition of the erosion, thrombosis rates, and response to ruxolitinib, a clinically available JAK1/2 inhibitor, in relation to genotype. Following experimental erosion, Jak2 V617F mice have greater impairment of endothelial barrier function and increased rates of arterial thrombosis. Neointimas in Jak2V617F mice exhibit increased apoptosis, NETosis, and platelet recruitment. Jak2 V617F mice treated with ruxolitinib show increased endothelial continuity and reduced apoptosis in the neointima comparable to levels in Jak2 WT. These observations provide new mechanistic insight into the pathophysiology of superficial erosion, the heightened risk for myocardial infarction in JAK2 V617F CHIP, and point the way to personalized therapeutics based on CHIP status. • Mechanisms of plaque erosion remain poorly understood. • Clonal hematopoiesis due to mutant JAK2 predisposes to myocardial infarction. • Mice bearing mutant myeloid Jak2 show increased liability to endothelial damage. • A JAK kinase inhibitor can mitigate superficial intimal damage due to Jak2 mutation. [ABSTRACT FROM AUTHOR]

• Cytotoxic therapy increases the risk for therapy-related myeloid neoplasms (t-MN). • While HSC-intrinsic effects are crucial, t-MN is also dependent on extrinsic factors. • Cytotoxic therapy drives senescence in the bone marrow microenvironment (BMME). • Current studies support a role for BMME senescence in the development of t-MN. • Targeting of senescent BMSCs may alleviate BM dysfunction and mitigate t-MN. Therapy-related myeloid neoplasms (t-MN) are a growing concern due to the continued use of cytotoxic therapies to treat malignancies. Cytotoxic therapies have been shown to drive therapy-induced senescence in normal tissues, including in the bone marrow microenvironment (BMME), which plays a crucial role in supporting normal hematopoiesis. This review examines recent work that focuses on the contribution of BMME senescence to t-MN pathogenesis, as well as offers a perspective on potential opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSCs) are polyfunctional, regenerating all blood cells via hematopoiesis throughout life. Clonal hematopoiesis (CH) is said to occur when a substantial proportion of mature blood cells is derived from a single dominant HSC lineage, usually because these HSCs have somatic mutations that confer a fitness and expansion advantage. CH strongly associates with aging and enrichment in some diseases irrespective of age, emerging as an independent causal risk factor for hematologic malignancies, cardiovascular disease, adverse disease outcomes, and all-cause mortality. Defining the molecular mechanisms underlying CH will thus provide a framework to develop interventions for healthy aging and disease treatment. Here, we review the most recent advances in understanding the molecular basis of CH in health and disease. Genome sequencing and genotyping/karyotyping studies have established that clonal hematopoiesis (CH) is characterized by mosaic postzygotic genomic alterations that include single-nucleotide variants/indels and mosaic chromosomal alterations that confer a fitness and expansion advantage in hematopoietic stem cells (HSCs). Emerging data suggest that DNA damage and inflammatory signaling (which are reciprocally related) resulting from aging processes, infection, lifestyle, inherited genetic variation, environmental exposures, or disease, are major selective pressures and drivers of epigenetic drift and lead to the emergence and expansion of CH-associated mutations in HSCs. CH is an emerging public health challenge that is prevalent in the aging population, independently increasing the risk of hematologic malignancy, cardiovascular disease, and worse disease outcomes. [ABSTRACT FROM AUTHOR]

Aging-elevated DNMT3A R882H-driven clonal hematopoiesis (CH) is a risk factor for myeloid malignancies remission and overall survival. Although some studies were conducted to investigate this phenomenon, the exact mechanism is still under debate. In this study, we observed that DNMT3A R878H bone marrow cells (human allele: DNMT3A R882H) displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult. DNMT3A R878H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation, especially TNF α insults. Mechanistically, we identified that RIPK1–RIPK3–MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNF α insults. Briefly, we elucidated the molecular mechanism driving DNMT3A R878H-based clonal hematopoiesis, which raises clinical value for treating DNMT3A R882H-driven clonal hematopoiesis and myeloid malignancies with aging. With aging, hematopoietic stem cells accumulate DNMT3A mutation with necroptosis resistance which results in clonal hematopoiesis, and this process can be aggravated by inflammation challenge. [Display omitted] [ABSTRACT FROM AUTHOR]

Somatic mutations have traditionally been associated with cancer, yet more recently, it was realized that they also appear in nontransformed cells beginning in early life. Remarkably, some of these mutations, commonly viewed as cancer driver mutations, are widely spread among cells of noncancerous tissues, sometimes affecting the majority of the tissue cells. This spreading process intensifies upon aging or exposure to extrinsic insults, such as UV irradiation, inhaling smoke, and inflammatory cues. Whereas classic driver mutations in normal cells are mostly viewed as a first step in the carcinogenesis process, here, we speculate that in certain states, they can play beneficial homeostatic roles while confronting stress and aging tissue repair. Somatic mutations are a universal phenomenon in cancer cells, yet they are surprisingly common in healthy cells. Mutated cell clones expand in a tissue at the expense of the normal cells and are thought to be poised for cancerous transformation. Mice harboring hotspot oncogenic mutations in TP53 are protected from carcinomas in the small bowel, suggesting an unrecognized homeostatic function of certain mutations traditionally known as cancer drivers. Rates and dynamics of some specific driver mutations in normal versus cancer human tissues are in-line with the notion of a positive homeostatic role, particularly under stress. Distinguishing beneficial from deleterious functions of somatic mutations, as well as the conditions and factors affecting these contrasting effects, may be of great value in understanding aging and cancer predisposition. [ABSTRACT FROM AUTHOR]

Genotyping of plasma cell-free DNA (cfDNA) is an increasingly important method to assess the tumor mutation status in colorectal cancer (CRC) patients. Clonal hematopoiesis (CH) releases non-tumor somatic mutations into blood, causing false positive results in cfDNA-based tumor genotyping. It is still not clear if CH should be examined in all CRC patients undergoing cfDNA analysis. We analyzed cfDNA KRAS , NRAS and BRAF genotypes in 236 metastatic CRC patients, who had matched tissue genotyping results, by next-generation sequencing using plasma cfDNA. The cfDNA-only mutations with allele frequencies (AFs) < 5% were highly suspicious for being CH-derived mutations. The origins of cfDNA mutations were confirmed by droplet digital polymerase chain reaction (ddPCR) using paired peripheral blood cells (PBCs) and CH-derived mutations were finally determined. One patient with a CH-derived mutation was followed up and the subpopulation of blood cells, in which CH was present, was investigated. Three CH-derived mutations, KRAS Q61H, KRAS G12D and KRAS G12V, were identified in the patient cohort. All three patients harboring corresponding CH-derived mutations had a prior chemotherapy history. The CH-derived KRAS G12V mutation in a patient was found only present in lymphocytes and persisting under treatment. For all cfDNA mutations, the CH-derived ones were clustered in the patients with < 5% mutation AF and prior chemotherapy. The prevalence of CH in CRC patients was limited, and prior chemotherapy was a contributing factor of CH. It is recommended for patients with < 5% mutation AF and prior chemotherapy to have genotyping analysis of their PBCs following plasma cfDNA genotyping. [ABSTRACT FROM AUTHOR]

The accumulation of acquired mutations is an inevitable consequence of the aging process, but its pathophysiological relevance has remained largely unexplored beyond cancer. Most of these mutations have little or no functional consequences, but in a few rare instances, a mutation may arise that confers a competitive advantage to a stem cell, leading to its clonal expansion. When such a mutation occurs in hematopoietic stem cells, it leads to a situation of clonal hematopoiesis, which has the potential to affect multiple tissues beyond the bone marrow, as the clonal expansion of the mutant stem cell is extended to circulating blood cells and tissue-infiltrating immune cells. Recent genomics and experimental studies have provided support to the notion that this somatic mutation-driven clonal hematopoiesis contributes to vascular inflammation and the development of atherosclerosis and related cardiovascular and cerebrovascular ischemic events. Here, we review our current understanding of this emerging cardiovascular risk modifier and the mechanisms underlying its connection to atherosclerosis development. • Somatic mutation-driven clonal hematopoiesis has emerged as an independent risk factor forcardiovascular disease. • Experimental studies are testing the hypothesis that clonal hematopoiesis promotes inflammation and atherosclerosis. • Mechanistic studies may provide rationale for the development of personalized preventive care strategies or therapies. • Further research is required to understand this new cardiovascular risk factor and its clinical management. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH), characterized by the accumulation of acquired somatic mutations in the blood, is associated with an elevated risk of aging-related diseases and premature mortality in non-cancer populations. Patients who undergo autologous hematopoietic cell transplantation (HCT) are also at high risk of premature onset of aging-related conditions. Therefore, we examined the association between pretreatment CH and late-occurring (≥1 year) nonrelapse mortality (NRM) after HCT. We evaluated pathogenic and likely pathogenic CH variants (PVs) in 10 patients who developed NRM after HCT and in 29 HCT recipient controls matched by age at HCT ± 2 years (median, 64.6 years; range, 38.5 to 74.7 years), sex (79.5% male), diagnosis (61.5% with non-Hodgkin lymphoma, 18.0% with Hodgkin lymphoma, and 20.5% with multiple myeloma), and duration of follow-up. We analyzed mobilized hematopoietic stem cell DNA in samples collected before HCT using a custom panel of amplicons covering the coding exons of 79 myeloid-related genes associated with CH. PVs with allele fractions >2% were used for analyses. Cases were significantly more likely than controls to have CH (70% versus 24.1%; P =.002), to have ≥2 unique PVs (60% versus 6.9%; P <.001), and to have PVs with allelic fractions ≥10% (40% versus 3.4%; P =.003). Here we provide preliminary evidence of an association between pre-HCT CH and NRM after HCT independent of chronologic age. Integration of CH analyses may improve the accuracy of existing pre-HCT risk prediction models, setting the stage for personalized risk assessment strategies and targeted treatments to optimally prevent or manage late complications associated with HCT. • Pretransplantation clonal hematopoiesis (CH) is associated with nonrelapse mortality. • The association appears to be independent of chronologic age. • Studies are needed to determine the utility of CH in transplantation risk prediction. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) is defined by the presence of somatic mutations in hematopoietic stem and progenitor cells (HSPC). CH is associated primarily with advancing age and confers an elevated risk of progression to overt hematologic malignancy and cardiovascular disease. Increasingly, CH is associated with a wide range of diseases driven by, and sequelae of, inflammation. Accordingly, there is great interest in better understanding the pathophysiologic and clinical relationship between CH, aging, and disease. Both observational and experimental findings support the concept that CH is a potential common denominator in the inflammatory outcomes of aging. However, there is also evidence that local and systemic inflammatory states promote the growth and select for CH clones. In this review, we aim to provide an up-to-date summary of the nature of the relationship between inflammation and CH, which is central to unlocking potential therapeutic opportunities to prevent progression to myeloid malignancy. [Display omitted] • Clonal hematopoiesis is associated with numerous adverse outcomes. • Pre-clinical data suggests that inflammation promotes clonal expansion, which in-turn supports an inflammatory phenotype. • Environmental sources of inflammation, including smoking, diet, and infections have been shown to enrich for CH. • Population studies indicate associations between CH and inflammatory diseases including vasculitis, gout, and arthritis. • Clinical trials targeting inflammation are underway to prevent adverse outcomes in individuals with CH. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) is defined by the presence of an expanded clonal hematopoietic cell population due to an acquired mutation conferring a selective growth advantage and is known to predispose to hematologic malignancy. In this review, we discuss sequencing methods for CH detection in bulk sequencing data and corresponding bioinformatic approaches for variant calling, filtering, and curation. We detail practical recommendations for CH calling. Finally, we discuss how improvements in CH sequencing and bioinformatic approaches will enable the characterization of CH trajectories, its impact on human health, and therapeutic approaches to mitigate its adverse effects. • Distinguishing low VAF (<2%) CH mutations from sequencing errors is difficult. • Sources of error in CH sequencing are diverse and occur at all steps of experiments. • Specialized somatic variant calling and filtering approaches improve CH detection. • Accurate low VAF mutation detection is required to study CH initiation and expansion. [ABSTRACT FROM AUTHOR]

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Anemia in elderly (AE), though often mild, is quite common and independently associated with important clinical outcomes, including decreased quality of life, risk of falls and fractures, cognitive decline, increased length of hospital stay, and even mortality. AE is generally overlooked, and hence undertreated, especially when comorbidities distract the attention of physicians and caregivers. This also partially reflects difficulties in dissecting the cause(s) of AE, which is typically multifactorial, as well as our limited diagnostic approach often categorizing AE as apparently "unexplained". Therapeutic approaches have been traditionally limited to transfusions, or supplementation with hematinics, including group B vitamins and iron. The latter has been largely underutilized, because of missing diagnosis of iron deficiency using inappropriate laboratory thresholds, as well as complex schedule and adverse effects associated with traditional preparations. After decades of stagnation, new oral and intravenous iron preparations look promising, particularly in the elderly. Moreover, a number of innovative anti-anemic drugs, like hepcidin modulators, Hypoxia Inducible Factor (HIF) stabilizers, and activin type II receptor agonists are entering the clinical arena and may substantially improve our therapeutic armamentarium to AE in the near future. [ABSTRACT FROM AUTHOR]

• Every cell in a person's body, including tumor cells, contains germline DNA. • Tumor-based sequencing panels can incidentally identify germline variants. • The term 'somatic' mutation panel is misleading and should no longer be used. With improvements in DNA sequencing technologies and the consequent reduction in costs, next generation sequencing is being utilized increasingly in panel-based testing to perform molecular profiling of tumors. Such tumor-based panels are often referred to as 'somatic' panels, but this term is misleading and should not be used, since not all DNA variants within a tumor are somatic in nature. Every cell in a person's body contains that person's germline DNA, including tumor cells. Moreover, tumor samples are invariably contaminated with blood, a tissue that can contain somatic mutations itself in a process now called clonal hematopoiesis. Differentiating between germline variants or tumor-associated somatic mutations versus clonal hematopoiesis can be challenging. In this review, we address how to interpret the results of somatic mutation panels, how to differentiate between germline and truly somatic events, and discuss the importance of this distinction. [ABSTRACT FROM AUTHOR]

• NGS hereditary cancer genetic testing can detect both germline and somatically acquired variants. • The chance of having a likely-somatic variant increased with age and with personal cancer history. • Precision in clinical genetic testing is required to deliver accurate germline testing results. Next-generation sequencing (NGS) hereditary pan-cancer panel testing can identify somatic variants, which exhibit lower allele frequencies than do germline variants and may confound hereditary cancer predisposition testing. This analysis examined the prevalence and characteristics of likely-somatic variants among 348,543 individuals tested using a clinical NGS hereditary pan-cancer panel. Variants showing allele frequencies between 10% and 30% were interpreted as likely somatic and identified in 753 (0.22%) individuals. They were most frequent in TP53, CHEK2 and ATM , commonly as C-to-T transitions. Among individuals who carried a likely-somatic variant and reported no personal cancer history, 54.2% (78/144) carried a variant in TP53, CHEK2 or ATM. With a reported cancer history, this percentage increased to 81.1% (494/609), predominantly in CHEK2 and TP53. Their presence was associated with age (OR=3.1, 95% CI 2.5, 3.7; p <0.001) and personal history of cancer (OR=3.3, 95% CI 2.7, 4.0; p <0.001), particularly ovarian cancer. Germline ATM pathogenic variant carriers showed significant enrichment of likely-somatic variants (OR=2.8, 95% CI 1.6, 4.9; p = 0.005), regardless of cancer status. The appearance of likely-somatic variants is consistent with clonal hematopoiesis, possibly influenced by cancer treatment. These findings highlight the precision required of diagnostic laboratories to deliver accurate germline testing results. [ABSTRACT FROM AUTHOR]

Acute Myeloid Leukemia, the most common form of acute leukemia in adults, is an aggressive hematopoietic stem cell malignancy that is associated with significant morbidity and mortality. Though AML generally presents de novo , risk factors include exposure to chemotherapy and/or radiation, as well as both familial and acquired bone marrow failure syndromes. Clonal Hematopoiesis (CH) refers to an expansion of blood or marrow cells resulting from somatic mutations in leukemia-associated genes detected in individuals without cytopenias or hematological malignancies. While CH is considered part of normal ageing, CH is also significantly associated with cardiovascular disease, solid tumors, and hematological malignancies. In this review, we will discuss evidence linking CH with the development of AML, as well as describe challenges in and strategies for monitoring patients with high risk CH mutations. [ABSTRACT FROM AUTHOR]

Abstract Transformation of myelodysplastic syndromes (MDS) into secondary acute myeloid leukemia (sAML) is defined by an arbitrary boundary of ≥20% bone marrow blasts but does not necessarily reflect a defined biological transition. The more obvious distinction lies between MDS patients that have an isolated bone marrow failure phenotype and those with excess blasts. Subtyping of MDS might be more accurately stratified into clonal cytopenias and oligoblastic leukemias, using the degree of dysplasia and blast percentage as risk features, respectively, rather than as diagnostic criteria. Transformation from MDS to sAML often involves clonal evolution or expansion of existing subclones that can be assessed by changes in variant allele frequencies of the somatic mutations that define them. There are a number of predictors for transformation that have been identified: these include mutations of genes in growth signaling pathways (NRAS , KRAS , PTPN11 , FLT3), mutations in genes more commonly observed in AML (NPM1 , WT1 , IDH2), certain cytogenetic abnormalities (monosomy 7, complex karyotype, loss of 17p). Gene expression profiles that divide MDS into two major categories identify a progenitor gene signature subtype associated with a high risk of AML transformation. Assessing for these genetic abnormalities may better identify MDS patients at greatest risk of transformation. [ABSTRACT FROM AUTHOR]

Acquired clonal chromosomal abnormalities (CAs) are usually considered to be disease-related. However, when a CA of this type is the only abnormality present (and especially in small clones), the clinical significance is unclear. Here, we review the literature on recurrent CAs whose significance is regularly subject to debate. Our objective was to help with their interpretation and develop guidelines for sex chromosome loss, trisomy 15, trisomy 8, deletion 20q and other isolated non-myelodysplastic neoplasm (MDS)-defining CAs. We suggest that non-MDS-defining CAs correspond to clonal hematopoiesis of indeterminate potential (CHIP) in the absence of cytopenia and clonal cytopenia of undetermined significance (CCUS) in the presence of cytopenia. Lastly, we review the literature on persistent polyclonal binucleated B-cell lymphocytosis; although usually benign, this condition may correspond to a premalignant state. [ABSTRACT FROM AUTHOR]

Highlights • The chemotherapy and radiation given at the time of hematopoietic cell transplantation (HCT) may increase the risk of an accelerated aging phenotype in long-term survivors. • Presence of clonal hematopoiesis (CH) before HCT may increase the risk of development of therapy-related myeloid neoplasm. • Late effects in HCT may be due to cellular senescence, acquired telomeropathy, stem cell exhaustion, or a combination of the above. ABSTRACT Hematopoietic cell transplantation (HCT) is increasingly utilized as a treatment for malignancies in the elderly population. At the same time, research has elucidated the impacts of HCT on bone marrow progenitor cells, one of which is accelerated aging. Clonal hematopoiesis has also been observed to occur in the aging population, both with and without HCT. The interplay between natural aging, clonal hemoatpoiesis, and the effects of HCT on the bone marrow, has not yet been addressed. Herein we explore this relationship, and its important clinical implications. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in healthy older individuals, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis.Objectives: This study investigated whether Tet2 mutations within hematopoietic cells can contribute to heart failure in 2 models of cardiac injury.Methods: Heart failure was induced in mice by pressure overload, achieved by transverse aortic constriction or chronic ischemia induced by the permanent ligation of the left anterior descending artery. Competitive bone marrow transplantation strategies with Tet2-deficient cells were used to mimic TET2 mutation-driven clonal hematopoiesis. Alternatively, Tet2 was specifically ablated in myeloid cells using Cre recombinase expressed from the LysM promoter.Results: In both experimental heart failure models, hematopoietic or myeloid Tet2 deficiency worsened cardiac remodeling and function, in parallel with increased interleukin-1beta (IL-1β) expression. Treatment with a selective NLRP3 inflammasome inhibitor protected against the development of heart failure and eliminated the differences in cardiac parameters between Tet2-deficient and wild-type mice.Conclusions: Tet2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure as a result of elevated IL-1β signaling. These data suggest that individuals with TET2-mediated clonal hematopoiesis may be at greater risk of developing heart failure and respond better to IL-1β-NLRP3 inflammasome inhibition. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) is the development of a certain cell lineage which is the cornerstone of hematologic malignancy especially myeloid neoplasms, however, can also be found in old age (6th-7th decade). CH is caused by many different somatic mutations most commonly in DNMT3A, TET2, ASXL1, SF3B1 and TP53. It is detected by different sequencing methods, the most commonly used ones are next generation sequencing (NGS) which can be whole exome, whole genome sequencing or a panel for certain genes. CH is divided into multiple categories depending on the clinical picture associated with it into: clonal monocytosis of undetermined significance (CMUS), clonal hematopoiesis of indeterminate significance (CHIP), clonal cytopenia and monocytosis of undetermined significance (CCMUS) and clonal cytopenia of undetermined significance (CCUS). In order to diagose CH, first other hematologic malignancies must be ruled out CH is also associated with many different entities including lung cancer and some studies have shown that COVID-19 infections are affected by CH. Certain traits and infections are associated with CH including smoking, obesity, and cardiovascular disease. A minority of patients with CH progress to a malignant process (between 0.5 %−2 %) which do not require treatment, however, any patient with CH should be kept under surveillance in order to detect any malignancy early and be treated accordingly. Clonal hematopoiesis (CH) is considered to be the predisposing factor for development of different hematologic neoplasms. With the help of NGS, patients with CH can be monitored more closely. Several studies have shown that these patients might develop hematologic neoplasms in their lifetime. It has been subdivided into multiple groups according to the clinical picture and/or blood counts. • Clonal hematopoiesis and its different types. • The new entity of clonal monocytosis of undetermined significance and that it is only recognized in ICC classification rather than the 55th edition on the WHO. • Clonal hematopoiesis plays a role not just in neoplasia but also in other comorbidities. [ABSTRACT FROM AUTHOR]

Knowledge about evolution of clonal hematopoiesis, which may drive malignant progression, is crucial for clinical decision-making. We investigated the landscape of clonal evolution by error-corrected sequencing on 7,045 sequential samples from 3,359 individuals in the prospective population-based Lifelines cohort, with a special focus on cytosis and cytopenia. Spliceosome (SRSF2/U2AF1/SF3B1) and JAK2 mutated clones show highest growth rates over a median 3.6-year period, while clone sizes for DNMT3A and TP53 increase only marginally, independent of cytosis or cytopenia. Nevertheless, large differences are observed between individuals carrying the same mutation, indicative of modulation by non-mutation-related factors. Clonal expansion is not dependent on classical cancer risk factors (e.g., smoking). Risk for incident myeloid malignancy diagnosis is highest for JAK2 , spliceosome, or TP53 mutations and absent for DNMT3A , and it is mostly preceded by cytosis or cytopenia. The results provide important insight into high-risk evolutionary patterns to guide monitoring of "CHIP" and "CCUS." [Display omitted] • Spliceosome (SF3B1 / SRSF2 / U2AF1) and JAK2 mutated clones show highest growth rates • DNMT3A and TP53 mutated clones increase only marginally over time • Clonal expansion is independent of general cancer risk factors or cytopenia/cytosis • Spliceosome, TP53, JAK2, and K/NRAS mutations confer highest risk for myeloid cancer Zeventer et al. report on longitudinal analyses of clonal hematopoiesis in 3,359 community-based individuals. Patterns of clonal evolution reveal large heterogeneity, irrespective of blood count abnormalities. Clonal expansion, patterns of sequential mutation acquisition, and the risk to develop myeloid malignancy are dependent on the specific mutated gene. The results warrant a gene-specific approach in the management of "CHIP" and "CCUS." [ABSTRACT FROM AUTHOR]

The accrual of somatic mutations is a byproduct of aging. When a clone bearing a somatic genetic alteration, conferring comparative competitive advantage, displays sufficient outgrowth to become detectable amongst an otherwise polyclonal background in the hematopoietic system, this is called clonal hematopoiesis (CH). Somatic genetic alterations observed in CH include point mutations in cancer related genes, mosaic chromosomal alterations or a combination of these. Interestingly, clonal hematopoiesis (CH) can also occur with somatic variants in genes without a known role in cancer and in the absence of a somatic genetic alteration through a process that has been described as 'genetic drift'. Clonal hematopoiesis of indeterminate significance (CHIP), is age-related and defined by the presence of somatic point mutations in cancer related genes, in the absence of cytopenias or a diagnosis of hematologic neoplasm, with a variant allele fraction ≥ 2 %. Remarkably, the increased mortality associated with CHIP is largely due to cardiovascular disease. Subsequently, CHIP has been associated with a myriad of age-related conditions such as Alzheimer's Disease, osteoporosis, CVA and COPD. CHIP is associated with an increased risk of hematologic malignancies, particularly myeloid neoplasms, with the risk rising with increasing clone size and clonal complexity. Mechanisms regulating clonal evolution and progression to hematologic malignancies remain to be defined. However, observations on context specific CH arising in the setting of bone marrow failure states, or on exposure to chemotherapy and radiation therapy, suggest that CH reflects context specific selection pressures and constraint-escape mechanisms. • Clonal hematopoiesis (CH) refers to the selective propagation of hematopoietic cells with an acquired genetic alteration. • CH is a precursor condition to hematologic malignancies, but only a minority of individuals will develop a malignancy. • CH is associated with an increased risk for many age-related diseases potentially due to associated increased inflammation. • The probability of CH is modified by inherited DNA variants, ancestry, and environmental exposures. • The mutational spectrum of CH is context specific reflecting distinct selection pressures. [ABSTRACT FROM AUTHOR]

Although mutations in RNA splicing genes occur frequently in patients with clonal cytopenias of unknown significance (CCUS) and myelodysplastic syndromes (MDS), very often additional common myeloid gene driver mutations are present at diagnosis. Thus, the clinical significance of isolated mutations in the most commonly mutated RNA splicing genes remains unknown. Here we report five unusual patients with an isolated mutation causing a loss of function of ZRSR2, a protein required for recognition of a functional 3′ splice site. Two of the patients had a diagnosis of CCUS and three patients had an MDS disorder characterized by low risk features and absence of complex cytogenetic abnor-malities. Notably, all five cases were characterized predominantly by macrocytic anemia. In addition, one CCUS patient followed for more than 15 years with a transfusion dependent macrocytic anemia was found to have an inactivating ZRSR2 mutation with an allele frequency of >60%. We conclude that the common clinical features of patients with an isolated mutation of ZRSR2 are a macrocytic anemia without leukopenia, thrombocytopenia or an increase in marrow blast percentage. At least in some cases, the presence of an isolated ZRSR2 mutation can accompany a dominant hematopoietic clone with a low risk for transformation to frank dysplasia or acute leukemia. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) is a result of the selective expansion of hematopoietic stem and progenitor cells (HSPCs) carrying somatic mutations originating from a primary HSC. The advent of modern genomic technologies has helped recognizing that CH is common in elderly healthy subjects as a result of the aging bone marrow (BM). CH in healthy subjects without abnormalities in blood counts is known as CH of indeterminate potential. CH is also seen in BM failure (BMF) disorders. Whether CH alarms for the risk to develop malignant evolution in BMF or creates an adaptation to selective pressure is a matter of controversy. As such, a continuum might exist from pre-malignant to malignant hematopoietic diseases. This review summarizes how somatic mutations and immune derangement in HSCs shape disease evolution and describes the complexity of disorders such as VEXAS as the prototypic tetrad of somatic mutations, morphologic features, inflammatory pathways and immune overshooting. In such a view, we interconnect the axis aging and immune-hematopoietic system, which all convey important clues for the risk to develop malignancies. • The pathogenesis of bone marrow failure syndromes intertwines genomic and immune aspects. • There is a continuum from clonal hematopoiesis, inflammation to overt hematological malignancies. • The alteration of several inflammatory pathways characterizes both bone marrow failure syndromes and VEXAS. [ABSTRACT FROM AUTHOR]

Life expectation of chronic myeloid leukemia patients in the tyrosine kinase inhibitors era is almost equal to that of healthy subjects. On the other hand, their long-term management must take into account a higher risk of adverse events, at least partly related to the treatment. Various studies reported a higher incidence of cardiovascular events in these patients. Clonal hematopoiesis is broadly considered a major independent risk factor for cardiovascular events. Of note, the underlying physiopathological mechanisms connect clonal hematopoiesis with a global proinflammatory status, triggering a vicious circle in which the somatic mutations and inflammation feed each other. All this considered, we investigated the occurrence of clonal hematopoiesis in chronic myeloid leukemia patients developing a cardiovascular event under tyrosine kinase inhibitor therapy. • Chronic myeloid leukemia (CML) long-term management is an emerging clinical issue. • Cardiovascular (CV) adverse events are recognized in CML patients on TKI therapy. • Clonal hematopoiesis (CH) could arise during the disease. • The vicious cycle of inflammation, CH and CV events needs to be considered. [ABSTRACT FROM AUTHOR]

Mosaic chromosomal alterations (mCAs) are the clonal expansion of large somatically acquired structural chromosomal changes present on the autosomes and sex chromosomes. Most studies of mCAs use existing genotype array intensity data from large populations to investigate potential risk factors and disease outcomes associated with mCAs. In this review, we perform a comprehensive examination of existing evidence for mCA disease and mortality associations and provide a framework for interpreting these associations in the context of important biases specific to mCA studies. Our goal is to motivate well-designed mCA studies to assist in unlocking the potential of mCAs to improve understanding of the effects of ageing and accelerate translational applications for improving public health. ● Mosaic chromosomal alterations (mCAs) are detectable in circulating leukocutes of apparently healthy adults. ● Accumulating evidence indicates mCAs could be associated with disease and mortality. ● Careful interpretation is warranted in studies of mCAs as many potential biases can result in spurious associations. [ABSTRACT FROM AUTHOR]

Therapy-related myeloid neoplasms (t-MN) account for approximately 10–15% of all myeloid neoplasms and are associated with poor prognosis. Genomic characterization of t-MN to date has been limited in comparison to the considerable sequencing efforts performed for de novo myeloid neoplasms. Until recently, targeted deep sequencing (TDS) or whole exome sequencing (WES) have been the primary technologies utilized and thus limited the ability to explore the landscape of structural variants and mutational signatures. In the past decade, population-level studies have identified clonal hematopoiesis as a risk factor for the development of myeloid neoplasms. However, emerging research on clonal hematopoiesis as a risk factor for developing t-MN is evolving, and much is unknown about the progression of CH to t-MN. In this work, we will review the current knowledge of the genomic landscape of t-MN, discuss background knowledge of clonal hematopoiesis gained from studies of de novo myeloid neoplasms, and examine the recent literature studying the role of therapeutic selection of CH and its evolution under the effects of antineoplastic therapy. Finally, we will discuss the potential implications on current clinical practice and the areas of focus needed for future research into therapy-selected clonal hematopoiesis in myeloid neoplasms. [Display omitted] • Therapy related myeloid neoplasms (t-MN) make up 10–20% of myeloid malignancies • Clonal hematopoiesis (CH) occurs at high frequency in t-MN • Whole genome sequencing characterizes complexity of t-MN genetic alterations • Triad of CH, chemotherapy selection and immune response contributes to t-MN [ABSTRACT FROM AUTHOR]

• U2AF1 CH is infrequent in age-related CH (<10 %) and commonly presents as CCUS.. • U2AF1 CH is common in males and frequently co-occurs with BCOR mutations (29 %; 86 % occurring in males). • U2AF1 mutant CH is associated with a high rate (25 %) and short latency (17.5 months) for progression to myeloid neoplasms. • U2AF1 CH occurs in the elderly and the context-specific occurrence in younger patients with TBD needs assessment. [ABSTRACT FROM AUTHOR]

DNMT3A mutations are frequent in cytogenetically normal acute myeloid leukemia (CN-AML) patients and can be present many years before the disease develops. However, the clinical significance of DNMT3A mutation burden in CN-AML remains unclear. In this study, 81 DNMT3A mutated adult CN-AML patients in their first complete remission (CR) were enrolled at our center from March 2005 to May 2015. All patients were identified as having DNMT3A exon 23 mutations, and R882H was the most frequent variant (n = 49, 60.49%). A total of 48 patients (48/81, 59.3%) were found to have DNMT3A mutations upon achieving CR. At the final follow-up exam, 40 patients remained in CR, 8 of which (8/81, 9.9%) were found to still have DNMT3A mutations. Analysis of the order of NPM1 , FLT3-ITD and DNMT3A mutations for different disease statuses revealed that DNMT3A might be the earliest mutation in leukemic cells. In addition, we determined the possible gene aberrations in 12 de novo and 2 relapsed samples using next-generation sequencing. NPM1 (5/12, 41.7%), FLT3-ITD (5/12, 41.7%) and CEBPA mutations (4/12, 33.3%) were the most frequent coexisting mutations. In the relapsed samples, additional genes aberrations could be observed, and some of them were never reported in AML patients. The 2-year overall survival (2-OS) for 81 DNMT3A mutated CN-AML patients was 39.0%. No differences was found in 2-OS (38.2% vs 41.6%, P = 0.2256) and 2-year disease free survival (2-DFS: 28.5% vs 34.3%, P = 0.1831) between patients with negative (n = 33) and positive DNMT3A mutation findings (n = 48) at the first CR. In summary, our findings indicated that DNMT3A mutation burden could persist in adult DNMT3A mutated CN-AML patients in long-term remission and that DNMT3A mutation was the early event in the development of leukemic cells. [ABSTRACT FROM AUTHOR]

We recently described the development of an inv(16) acute myeloid leukemia (AML) in a CBL mutated clonal hematopoiesis. Here, we further characterized the clonal composition and evolution of the AML based on the genetic information from the bulk specimen and analyses of individual bone marrow cells for mutations in CAND1 , PTPRT , and DOCK6 . To control for allele dropout, heterozygous polymorphisms located close to the respective mutation loci were assessed in parallel. The clonal composition concluded from exome sequencing suggested a proliferation advantage associated with the acquisition of mutations in CAND1 , PTPRT , and DOCK6 . Out of 102 single cell sequencing reactions on these mutations and the respective polymorphisms, analyses yielded conclusive results for at least 2 mutation sites in 12 cells. The single cell genotyping not only confirmed the co-occurrence of the PTPRT, CAND1 and DOCK6 mutations in the same AML clone but also revealed a clonal hierarchy, as the PTPRT mutation was likely acquired after the CAND1 and DOCK6 mutations. This insight had not been possible based solely on the exome sequencing data and suggests that the mutation in PTPRT , which encodes a STAT3-inhibiting protein tyrosine phosphatase, contributed to the AML development at a later stage by enhancing proliferation. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) refers to the disproportionate expansion of hematopoietic stem cell clones and their corresponding progeny following the acquisition of somatic mutations. CH is common at the time of diagnosis in patients with blood cancers, including multiple myeloma (MM) and lymphoma. The presence of CH mutations correlates with IL-6 mediated inflammation and may result in lymphoma or MM modulation through microenvironment effects or by manifestations of the mutations themselves within the founding tumor clone. As might be expected with a variety of mutations and multiple potential mechanisms, CH exerts context-dependent effects, being protective in some settings and harmful in others. Though CH is very common in patients with hematologic malignancies, how it intersects with therapy and the natural disease course of these cancers are active areas of investigation. In lymphomas and MM specifically, patients have high rates of CH at diagnosis and are subsequently exposed to therapies, such as cytotoxic chemotherapy, that can cause CH progression to overt hematologic malignancy. The expanding diversity of treatment modalities for these cancers also increases the opportunities for CH to impact clinical outcome and modulate clinical responses. Here we review the basic biology and known health effects of CH, and we focus on the clinical relevance of CH in lymphoma and MM. [ABSTRACT FROM AUTHOR]

Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20–25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin samples in 22 patients. We found somatic mutations in 16 patients (72.7%) with a median disease duration of 1 year; of these, 12 (66.7%) were patients with pediatric-onset aAA. Fifty-eight mutations in 51 unique genes were found primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA , with seven mutations. Only two mutations were in genes recurrently mutated in myelodysplastic syndrome. Two patients had oligoclonal loss of the HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B (p.N642H) and CAMK2G (p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging—immune escape and increased proliferation. Our findings expand conceptual understanding of this nonneoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes and for designing personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) is a clonal expansion of single hematopoietic stem cells (HSC) with germline or somatic mutations accumulated in specific genes, which usually leads to clonal dominance via multiple biological pathways and increases the risk of developing hematological malignancies. With the advancement of Next Generation Sequencing (NGS) technology, CH can be widely detected in healthy individuals, many patients complicated with bone marrow failure (BMF), or even in those with myeloproliferative neoplasm (MPN) and therapy-related MDS/AML (t-MDS/AML). Recently, several proof-of-concept studies showed that it is likely to discriminate the CH with high risk developing malignancy through predictive models many years before its onset. Additionally, it has been shown that the CH-related premalignant clones can be abated or eradicated through chemical or genetic measures in animal models, thereby providing an insightful idea for preventing leukemogenesis. However, in despite of these advancements, the clinical implication and early diagnosis of CH for predicting hematological malignancies remain to be more investigated. In this review, we will first review the brief history, risk factors and molecular mechanisms of CH. Then, we will discuss the involved biological process of CH in bone marrow failure diseases, MPN and t-MDS/AML, pointing to its clinical implication. Finally, we will discuss the advancement of early detection of CH at premalignant stage for predicting hematological malignancies, and express perspectives and challenges for early intervention of CH in the future. [ABSTRACT FROM AUTHOR]

• CHIP refers to the acquisition of somatic, leukemia associated driver mutations in hematopoietic stem and progenitor cells, in patients without an underlying hematological neoplasm. • CHIP is associated with a low but definite risk of developing myeloid and lymphoid neoplasms, with evolution rates dependant on the nature of mutation(s), mutational variant allele fractions and several cell intrinsic and extrinsic clonal selection pressures. • CHIP is associated with an increased all-cause mortality, largely due to cardiovascular and cerebrovascular events (endothelial dysfunction). • CHIP prevalence rates increase with age and depend on the sequencing technologies being used, with newer techniques demonstrating that prevalence is nearly ubiquitous in the elderly. Clonal hematopoiesis (CH) defines a population of hematopoietic cells with one or more somatic mutations/copy number alterations that can expand with time and under positive clonal selection pressures. The term CH of indeterminate potential (CHIP) operationally describes somatic mutations in leukemia-associated driver genes in hematopoietic stem cells with variant allele frequencies (VAF) of ≥ 2%, without evidence for an underlying hematological malignancy. Risk factors for CHIP include aging, inflammation, male sex, cigarette smoking, history of cancer and cancer treatments, germline predisposition states, among others. CHIP is a premalignant condition, with a low but definite risk of hematologic malignancies and is associated with increased all-cause mortality, largely due to cardiovascular disease and associated endothelial dysfunction. Here we review recent advances in CHIP, including diagnostic, prognostic, and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Clonal hematopoiesis (CH) – a biological state in which one or a small number of hematopoietic stem or progenitor cells contribute disproportionately to blood cell production, usually as a result of somatic gene mutations in the stem cells – is often considered to be a precursor to myeloid neoplasia, especially myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, the majority of people with CH never develop an overt myeloid neoplasm, and CH can be a precursor to lymphoid cancers as well as myeloid neoplasms. In addition, CH increases all-cause mortality and augments the risk of several non-neoplastic medical conditions, including atherosclerotic cardiovascular disease. CH can arise during aging, or in the context of an inherited marrow failure syndrome, aplastic anemia, or hematopoietic cell transplantation. Risk factors for progression of CH to myeloid neoplasia include larger clone size; the presence of a TP53, IDH1/2, or splicing mutation; multiple mutations; and associated cytopenias or abnormal red blood cell indices. The receipt of genotoxic chemotherapy or radiation, which can promote clonal expansion of mutant clones at the expense of healthy progenitor cells, may result in therapy-related MDS/AML. [ABSTRACT FROM AUTHOR]

Paraspeckles are membraneless organelles formed through liquid-liquid phase separation and consist of multiple proteins and RNAs, including NONO, SFPQ, and NEAT1. The role of paraspeckles and the component NONO in hematopoiesis remains unknown. In this study, we show histone modifier ASXL1 is involved in paraspeckle formation. ASXL1 forms phase-separated droplets, upregulates NEAT1 expression, and increases NONO- NEAT1 interactions through the C-terminal intrinsically disordered region (IDR). In contrast, a pathogenic ASXL mutant (ASXL1-MT) lacking IDR does not support the interaction of paraspeckle components. Furthermore, paraspeckles are disrupted and Nono localization is abnormal in the cytoplasm of hematopoietic stem and progenitor cells (HSPCs) derived from ASXL1-MT knockin mice. Nono depletion and the forced expression of cytoplasmic NONO impair the repopulating potential of HSPCs, as does ASXL1-MT. Our study indicates a link between ASXL1 and paraspeckle components in the maintenance of normal hematopoiesis. [Display omitted] • Wild-type ASXL1 has a long IDR in C terminus and participates in phase separation • Wild-type ASXL1 binds to NONO/SFPQ and supports NONO-NEAT1 interaction • Mutant ASXL1 lacking IDR disrupts paraspeckle formation in hematopoietic cells • Dysfunction of NONO or ASXL1 impairs repopulation ability of HSPCs Yamamoto et al. show that ASXL1 undergoes phase separation through its C-terminal intrinsic disordered region (IDR) and supports paraspeckle formation. A pathogenic ASXL1 mutant lacking IDR inhibits efficient paraspeckle formation. These findings define ASXL1 function and provide insights into the pathogenesis of hematopoietic disorders with ASXL1 mutations. [ABSTRACT FROM AUTHOR]

Bone marrow failure syndromes (BMF) are a group of conditions characterized by inefficient hematopoiesis frequently associated with extra-hematopoietic phenotypes and variable risk of progression to myeloid malignancies. They can be acquired or inherited and mediated by either cell extrinsic factors or cell intrinsic impairment of hematopoietic stem cell (HSC) function. The pathophysiology includes immune-mediated attack (e.g., acquired BMFs) or germline defects in DNA damage repair machinery, telomeres maintenance or ribosomes biogenesis. (e.g., inherited BMF). Clonal hematopoiesis (CH) that frequently accompanies BMF may provide a mechanism of improved HSC fitness through the evasion of extracellular pressure or somatic reversion of germline defects. The mechanism for the CH selective advantage differs depending on the condition in which it occurs. However, this adaptation mechanism, particularly when involving putative oncogenes or tumor suppressors, may lead to increased risk of myeloid malignancies. Surveillance and early detection of leukemogenic clones may lead to timely implementation of curative therapies and improved survival. [ABSTRACT FROM AUTHOR]