Academic literature on the topic 'Clonal hematopoiesis of indeterminate potential'

Some random mutations can confer a selective advantage to a hematopoietic stem cell. As a result, mutated hematopoietic stem cells can give rise to a significant proportion of mutated clones of blood cells. This event is known as “clonal hematopoiesis.” Clonal hematopoiesis is closely associated with age, and carriers show an increased risk of developing blood cancers. Clonal hematopoiesis of indeterminate potential is defined by the presence of clones carrying a mutation associated with a blood neoplasm without obvious hematological malignancies. Unexpectedly, in recent years, it has emerged that clonal hematopoiesis of indeterminate potential carriers also have an increased risk of developing cardiovascular disease. Mechanisms linking clonal hematopoiesis of indeterminate potential to cardiovascular disease are only partially known. Findings in animal models indicate that clonal hematopoiesis of indeterminate potential-related mutations amplify inflammatory responses. Consistently, clinical studies have revealed that clonal hematopoiesis of indeterminate potential carriers display increased levels of inflammatory markers. In this review, we describe progress in our understanding of clonal hematopoiesis in the context of cancer, and we discuss the most recent findings linking clonal hematopoiesis of indeterminate potential and cardiovascular diseases.

Abstract Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.

Abstract Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.

Abstract Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.

Hematopoietic stem cells (HSCs) ensure the coordinated and balanced production of all hematopoietic cell types throughout life. Aging is associated with a gradual decline of the self-renewal and regenerative potential of HSCs and with the development of clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP) is a term defining the clonal expansion of genetically variant hematopoietic cells bearing one or more gene mutations and/or structural variants (such as copy number alterations). CHIP increases exponentially with age and is associated with cancers, including hematologic neoplasia, cardiovascular and other diseases. The presence of CHIP consistently increases the risk of hematologic malignancy, particularly in individuals who have CHIP in association with peripheral blood cytopenia. Key words: hematopoiesis, hematopoietic stem cells, clonal hematopoiesis, gene mutations, next generation sequencing.

AbstractObjectivesThe 2017 Workshop of the Society for Hematopathology/European Association for Hematopathology aimed to review premalignant clonal hematopoietic proliferations.MethodsThe workshop panel reviewed 27 cases of clonal proliferations of indeterminate significance or potential (18 myeloid, nine lymphoid) and rendered consensus diagnoses.ResultsImmunophenotyping and genetic studies on peripheral blood, bone marrow, and lymph node samples have led to the incidental detection of small clonal populations in asymptomatic individuals. These premalignant clonal myeloid and lymphoid proliferations include monoclonal gammopathy of uncertain significance, monoclonal B-cell lymphocytosis, in situ follicular neoplasia, in situ mantle cell neoplasia, clonal hematopoiesis of indeterminate potential, and clonal cytopenia of undetermined significance.ConclusionsCurrent diagnostic criteria for the diagnoses of premalignant clonal hematopoietic proliferations are reviewed and discussed in the context of the cases presented at the workshop.

Le vieillissement est associé à l’acquisition par les cellules souches hématopoïétiques (CSH) de mutations somatiques et d’altérations chromosomiques. Dans certains cas, l’acquisition d’une de ces anomalies confère à la CSH un avantage d’auto-renouvellement et de prolifération conduisant au développement d’une hématopoïèse clonale. Le terme d’hématopoïèse clonale de potentiel indéterminé (Clonal Hematopoiesis of indeterminate potential - CHIP) caractérise la détection dans le sang d’un clone portant une mutation somatique sur un gène associé aux leucémies avec une fréquence allélique ≥2 % mais en absence de tout critère diagnostique d’une hémopathie maligne. Les CHIP ont été associées à une augmentation de la mortalité globale qui serait principalement liée à la survenue d’évènements cardiovasculaires (ECV). Les CHIP participeraient notamment à la physiopathologie de l’athérothrombose et des insuffisances cardiaques (IC) en exacerbant le profil inflammatoire des monocytes et des macrophages mutés avec une surexpression des interleukines 1β, 6 et 18, consécutivement à une hyperactivation de l’inflammasome NLRP3. Plus récemment, la perte mosaïque du chromosome Y (mosaic Loss Of Y - mLOY) dans les leucocytes a également été associée aux ECV en favorisant un phénotype pro-fibrotique des macrophages.Dans un premier axe de travail, nous avons étudié l’association de la CHIP et de la mLOY avec le risque d’infarctus du myocarde (IDM+) dans une cohorte de 446 participants. Notre étude n’a pas retrouvé d’association statistiquement significative entre la CHIP ou la mLOY et l’inflammation, l’athérome ou encore l’incidence d’évènements athérothrombotiques, suggérant que l’effet de la CHIP ou de la mLOY est moins important que celui des facteurs de risque cardiovasculaire traditionnels. Cependant, nous avons observé que les hommes pourraient développer un IDM de façon plus précoce lorsqu’ils sont porteurs de CHIP s’ils ne présentent pas par ailleurs de mLOY.Dans un second axe de travail, nous avons étudié dans des modèles murins le rôle des CHIP dans la physiopathologie de l’IC à fraction d’éjection préservée (ICFEp). Nous avons utilisé un protocole d’induction de l’ICFEp combinant un régime de croquettes riches en graisse et l’infusion d’angiotensine II appliqué à des souris avec ou sans CHIP. Nos expériences n’ont pas montré d’effet significatif de la CHIP pour induire une ICFEp.Enfin, afin de déterminer si d’autres cellules que les monocytes et les macrophages pouvaient participer à la physiopathologie des ECV associées aux CHIP, nous avons cherché à savoir si les polynucléaires neutrophiles porteurs des mutations de CHIP pourraient avoir un rôle dans la survenue des ECV, notamment via l’émission de Neutrophil Extracellular Traps (NETs). Dans un échantillon de 81 patients IDM+, la présence de CHIP était significativement associée à l’augmentation de marqueurs plasmatiques des NETs (histone H3 citrullinée et complexe myélopéroxydase + ADN). Dans des modèles murins, la CHIP était associée à une augmentation non significative du pourcentage de NETs formés après stimulation des neutrophiles ex vivo à la ionomycine
Aging is associated with the acquisition by hematopoietic stem cells (HSCs) of somatic muta-tions and chromosomal alterations. In some cases, the acquisition of one of these abnormali-ties gives the HSC a self-renewal and proliferation advantage leading to the development of clonal hematopoiesis. The term Clonal Hematopoiesis of Indeterminate Potential (CHIP) characterizes the detection in the blood of a clone carrying a somatic mutation in one gene associated with leukemias with a variant allele frequency ≥2% but in the absence of any di-agnostic criteria for a hematological malignancy. CHIP have been associated with increased overall mortality which would be mainly related to the occurrence of cardiovascular events (CVE). CHIP would particularly participate in the pathophysiology of atherothrombosis and heart failures (HF) by exacerbating the inflammatory profile of mutated monocytes and macrophages with overexpression of interleukins 1β, 6, and 18, following hyperactivation of the NLRP3 inflammasome. More recently, the mosaic loss of Y chromosome (mLOY) in leu-kocytes has also been associated with CVE by promoting a pro-fibrotic phenotype of macro-phages.In a first line of work, we studied the association of CHIP and mLOY with the risk of myocar-dial infarction (MI+) in a cohort of 446 participants. Our study did not find a statistically sig-nificant association between CHIP nor mLOY and inflammation, atherosclerosis, or the inci-dence of atherosclerotic events, suggesting that the effect of CHIP or mLOY is less important than that of traditional cardiovascular risk factors. However, we observed that men who are carriers of CHIP might develop MI earlier if they do not carry mLOY on the other hand.In a second line of work, we investigated in mouse models the role of CHIP in the pathophys-iology of heart failure with preserved ejection fraction (HFpEF). We used an HFpEF induction protocol combining a high-fat diet and angiotensin II infusion applied to mice with or without CHIP. Our experiments did not show a significant effect of CHIP in inducing HFpEF.Finally, to investigate whether cell types other than monocytes and macrophages are in-volved in the pathophysiology of CVE associated with CHIP, we aimed to determine whether neutrophils carrying CHIP mutations could play a role in the occurrence of CVE, particularly through the release of Neutrophil Extracellular Traps (NETs). In a sample of 81 MI+ patients, the presence of CHIP was significantly associated with an increase in plasmatic markers of NETs (citrullinated histone H3 and myeloperoxidase + DNA complex). In mouse models, CHIP was associated with a non-significant increase in the percentage of NETs formed after ex vivo stimulation of neutrophils with ionomycin

Acute lymphoblastic leukemia (ALL) has been established as the most common acute leukemia in children, accounting for 80–85% of cases. ALL occurs mostly in children and it is considered as a high-risk disease in the elderlies. ALL is characterized by a clonal disorder where the normal hematopoiesis is replaced by a malignant clonal expansion of lymphoid progenitors. Although many therapeutic strategies have been established to treat ALL leading to improved survival rates, the short-term and long-term complications derived from treatment toxicity represent a critical risk for patients. The treatment-related toxicity suggests a need for the development of new therapy strategies to effectively treat high-risk and low-risk disease. Nowadays, an important approach is focused on the identification of molecules involved in the mechanisms that lead to leukemia generation and progression to determine potential targets at the transcriptional level. MicroRNAs (miRNAs) are a group of key molecules that regulate signaling pathways related to lymphopoiesis. miRNAs participate in the regulation of hematopoietic differentiation and proliferation, as well as their activity. The present review details the recompilation of evidences about the relation between miRNAs and lymphopoiesis, ALL development and progression in order to propose and explore novel strategies to modulate ALL-related miRNA levels as a therapeutic approach.