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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]

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]

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]

• 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 hematopoietic expansion (CHIP) is common in older people. • CHIP is associated with greater risk for hematological malignancies. • CHIP mutations are frequently found in epigenetic modifier genes such as DNMT3A. • CHIP mutations exert pleiotropic effects on leukemogenesis. • Pathogenic CHIP mutations may affect the clinical course of the patients. Recent genomics studies have revealed that clonal hematopoietic expansion due to recurrent somatic mutations in hematopoietic cells are common in older people without evidence of hematological malignancies. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), is associated with greater risk for hematological malignancy and cardiovascular diseases, leading to decreased overall survival of the affected individuals. The most frequently mutated genes in CHIP cases include genes associated with epigenetic modification, cell signaling, DNA damage response and RNA splicing, which are all recurrently mutated in myeloid malignancies. Recent findings suggest that these genetic alleles exert pleiotropic effects on hematopoietic stem cell (HSC) functions, transcriptional regulations, DNA damage responses and resistance to cellular stresses. Recent studies have uncovered the clinical relevance of CHIP in various settings during the management of hematological malignancies. Elucidating overall picture of clonal evolution based on CHIP will help developing preventive measures and novel treatments for hematological malignancies. [ABSTRACT FROM AUTHOR]