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American Journal of Hematology Jun 2023Clonal hematopoiesis (CH) refers to age-associated expansion of somatic variants in hematopoietic stem and progenitor cells (HSPC).
CONDITION OVERVIEW
Clonal hematopoiesis (CH) refers to age-associated expansion of somatic variants in hematopoietic stem and progenitor cells (HSPC).
DIAGNOSIS
CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in HSPCs at a variant allele frequency ≥2%.
CLINICAL ASSOCIATIONS
CH is associated with increased occurrence of several hematological conditions such as cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and non-hematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease, ischemic congestive heart failure, venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, gout, with a potential protective effect in Alzheimer's disease (AD).
MANAGEMENT RECOMMENDATIONS
As of now, there is limited prospective data for CH testing; however, CH detection is becoming increasingly prevalent due to ubiquitous use of somatic and germline NGS testing. This in addition to data suggesting that therapy related myeloid neoplasm (tMN) in many cases is preceded by the detection of CH clones, has led to the establishment of CH clinics at several institutions. At our institution, on a research basis, we currently recommend testing for CH for individuals with persistent (≥4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation and chimeric antigen receptor T cell (CAR-T) therapy and to assess as to whether or not, potential germline mosaic variants actually represent CH.
Topics: Humans; Clonal Hematopoiesis; Diabetes Mellitus, Type 2; Prospective Studies; Hematopoiesis; Clone Cells; Mutation
PubMed: 36938794
DOI: 10.1002/ajh.26915 -
Journal of Cancer 2018To measure hematologic parameters derived from the white blood cell (WBC) count and differential count (DC) as prognostic factors for survival in patients with stage IB...
To measure hematologic parameters derived from the white blood cell (WBC) count and differential count (DC) as prognostic factors for survival in patients with stage IB and IIA cervical cancer. We retrospectively examined demographic, clinicopathologic, and laboratory parameters in a cohort of 233 patients with International Federation of Gynecology and Obstetrics stage IB and IIA cervical cancer who underwent surgical resection. We further assessed the effects of the WBC count and DC-derived hematologic parameters on progression-free survival (PFS) and overall survival (OS) after controlling for other parameters. Patients were followed up for a median of 46.6 months (range, 9-142 months). The Kaplan-Meier estimates of PFS and OS at 5 years were 88.5% and 92.3%, respectively. In a multivariate analysis, we identified the absolute monocyte count (AMC) (hazard ratio [HR], 11.78; <0.001) and tumor size (HR, 5.41; = 0.003) as the strongest prognostic factors affecting PFS. We also identified AMC (HR, 23.29; <0.001), tumor size, (HR, 5.27; = 0.033), and lymph node involvement (HR, 3.90; = 0.027) as the strongest prognostic factors affecting OS. AMC remained prognostic with respect to PFS or OS in a Cox model that controlled for the neutrophil-lymphocyte ratio or lymphocyte-monocyte ratio, although neither ratio was a significant prognostic factor for survival. Monocytosis and an increased tumor size were found to be independent prognostic factors affecting both PFS and OS in patients with stage IB and IIA cervical cancer.
PubMed: 29290770
DOI: 10.7150/jca.22234 -
Frontiers in Oncology 2021Atypical chronic myelogenous leukemia (aCML), negative is a rare myelodysplastic/myeloproliferative neoplasm, usually manifested with hyperleukocytosis without... (Review)
Review
Atypical chronic myelogenous leukemia (aCML), negative is a rare myelodysplastic/myeloproliferative neoplasm, usually manifested with hyperleukocytosis without monocytosis or basophilia, organomegaly, and marked dysgranulopoiesis. In this review, we will discuss the classification and diagnostic criteria of aCML, as these have been formulated during the past 30 years, with a focus on the recent advances in the molecular characterization of the disease. Although this entity does not have a definitive molecular profile, its molecular characterization has contributed to a better understanding and more accurate classification and diagnosis of aCML. At the same time, it has facilitated the identification of adverse prognostic factors and the stratification of patients according to their risk for leukemic transformation. What is more, the molecular characterization of the disease has expanded our therapeutic choices, thoroughly presented and analyzed in this review article.
PubMed: 34868917
DOI: 10.3389/fonc.2021.722507 -
Cell Metabolism May 2014Obesity is associated with infiltration of macrophages into adipose tissue (AT), contributing to insulin resistance and diabetes. However, relatively little is known...
Obesity is associated with infiltration of macrophages into adipose tissue (AT), contributing to insulin resistance and diabetes. However, relatively little is known regarding the origin of AT macrophages (ATMs). We discovered that murine models of obesity have prominent monocytosis and neutrophilia, associated with proliferation and expansion of bone marrow (BM) myeloid progenitors. AT transplantation conferred myeloid progenitor proliferation in lean recipients, while weight loss in both mice and humans (via gastric bypass) was associated with a reversal of monocytosis and neutrophilia. Adipose S100A8/A9 induced ATM TLR4/MyD88 and NLRP3 inflammasome-dependent IL-1β production. IL-1β interacted with the IL-1 receptor on BM myeloid progenitors to stimulate the production of monocytes and neutrophils. These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1β signaling axis could reduce AT inflammation and insulin resistance in obesity.
Topics: Adipose Tissue; Animals; Bone Marrow; Carrier Proteins; Cell Proliferation; Humans; Inflammasomes; Interleukin-1beta; Macrophages; Male; Mice; Mice, Inbred C57BL; Monocytes; Myeloid Differentiation Factor 88; Myelopoiesis; NLR Family, Pyrin Domain-Containing 3 Protein; Neutrophils; Obesity; Receptors, Interleukin-1; Toll-Like Receptor 4
PubMed: 24807222
DOI: 10.1016/j.cmet.2014.03.029 -
European Journal of Pediatrics Sep 2021We report the clinical characteristics and management of fourteen neonates and very young infants with COVID-19. Although all presented with mild symptoms and did not...
We report the clinical characteristics and management of fourteen neonates and very young infants with COVID-19. Although all presented with mild symptoms and did not require specific treatment, most of them had abnormal laboratory and radiological findings. Ten infants presented with neutropenia and/or monocytosis but none with lymphopenia. Transient hypertriglyceridemia and/or prolonged viral shedding were detected in 9 patients.Conclusion: Based to our experience, COVID-19 is mild in very young infants and might have distinct laboratory findings. What is Known: • SARS-CoV-2 in infants is a mild disease. • The period of transmission is approximately 2 weeks. What is New: • Very young age is not a risk factor for severe COVID-19 but could be associated with prolonged viral shedding. • Neutropenia and monocytosis are distinct characteristics of COVID-19 in very young infants.
Topics: COVID-19; Humans; Infant; Infant, Newborn; Risk Factors; SARS-CoV-2
PubMed: 33786658
DOI: 10.1007/s00431-021-04042-x -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2011The systemic autoimmune disease such as systemic lupus erythematosus (SLE) is characterized by the deposition of immune complexes in multiple organs. Fcγ receptors... (Review)
Review
The systemic autoimmune disease such as systemic lupus erythematosus (SLE) is characterized by the deposition of immune complexes in multiple organs. Fcγ receptors (FcγR) recognize the Fc portion of IgG and are important in determining the response of leukocytes to deposited immune complexes. FcγR also provide positive and negative regulation of immune cell responses. The activatory FcγR including the FcR common γ chain take balance with Fcγ RIIB, the only inhibitory FcγR. Development of lupus-like autoimmune disease as well as monocytosis in BXSB mice is dependent on the activatory and inhibitory FcγR. In human SLE, dysregulated expression of FcγRIIB on memory B cells is reported and numbers of associations with genetic polymorphism are also reported. The cell-specific modulation of these activatory or inhibitory FcγRs are expected for the new therapeutic strategy in autoimmune diseases.
Topics: Animals; B-Lymphocytes; Humans; Immunologic Memory; Lupus Erythematosus, Systemic; Polymorphism, Genetic; Receptors, IgG
PubMed: 21372507
DOI: 10.2177/jsci.34.1 -
Virchows Archiv : An International... Dec 2023Differential diagnosis of clonal versus reactive cytopenia and monocytosis, respectively, frequently presents a diagnostic challenge. With the two recent classifications...
Differential diagnosis of clonal versus reactive cytopenia and monocytosis, respectively, frequently presents a diagnostic challenge. With the two recent classifications of myeloid disorders, mutational analysis has gained importance as a diagnostic tool. However, reports on its utility on trephine bone marrow biopsies (BMB) are sparse. The aim of our proof of principle study was to determine the suitability of targeted sequencing for the longitudinal evaluation of cytopenia and monocytosis and demonstration of clonal evolution on sequential BMB. Seventy-seven EDTA-decalcified BMB of 33 patients with peripheral cytopenia and/or monocytosis, including at least one follow-up biopsy/patient, were included. Initial morphological diagnoses were idiopathic cytopenia of undetermined significance (ICUS, 8 cases), MDS (without blast increase, 7 cases), MDS with increased blasts/excess blasts (MDS-IB/EB) (11 cases), and CMML (7 cases). Thirty-one genes relevant for myeloid disorders were examined using two custom AmpliSeq NGS panels. Mutations were found in the initial BMB of 5/8 cases of ICUS, thus changing the diagnosis to clonal cytopenia of unknown significance (CCUS), 5/7 MDS, 10/11 MDS-IB/EB, and 7/7 CMML. Clonal evolution was observed in 14/33 (42%) cases, mostly associated with disease progression. None of the wild-type patients acquired mutations during follow-up. NGS-based mutation profiling is a robust diagnostic tool for BMB and provides valuable additional information, especially for cases with no/minimal dysplasia, and for better risk stratification of MDS. Tracking variant allele frequency and appearance of mutations over time allows for observing clonal evolution or relapse.
Topics: Humans; Bone Marrow; Myelodysplastic Syndromes; Mutation; Clonal Evolution; Biopsy
PubMed: 37610626
DOI: 10.1007/s00428-023-03627-1 -
American Journal of Hematology Jun 2018Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative... (Review)
Review
DISEASE OVERVIEW
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%-20% over 3-5 years).
DIAGNOSIS
Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while >90% have gene mutations. Mutations involving TET2 (∼60%), SRSF2 (∼50%), ASXL1 (∼40%) and the oncogenic RAS pathway (∼30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over-all survival.
RISK STRATIFICATION
Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM), and the CMML specific prognostic model (CPSS-Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count > 10 × 10 /L, hemoglobin <10 gm/dL, platelet count <100 × 10 /L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into 4 groups; high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.
RISK-ADAPTED THERAPY
Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of ∼30%-40% and complete remission rates of ∼7%-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.
Topics: Antimetabolites, Antineoplastic; Disease Management; Humans; Leukemia, Myelomonocytic, Chronic; Prognosis; Risk Assessment; Stem Cell Transplantation; Transplantation, Homologous; Treatment Outcome
PubMed: 29878489
DOI: 10.1002/ajh.25104 -
Frontiers in Immunology 2021, the causative agent of scrub typhus, is a neglected, obligate intracellular bacterium that has a prominent tropism for monocytes and macrophages. Complications often...
, the causative agent of scrub typhus, is a neglected, obligate intracellular bacterium that has a prominent tropism for monocytes and macrophages. Complications often involve the lung, where interstitial pneumonia is a typical finding. The severity of scrub typhus in humans has been linked to altered plasma concentrations of chemokines which are known to act as chemoattractants for myeloid cells. The trafficking and function of monocyte responses is critically regulated by interaction of the CC chemokine ligand 2 (CCL2) and its CC chemokine receptor CCR2. In a self-healing mouse model of intradermal infection with the human-pathogenic Karp strain of , we investigated the role of CCR2 on bacterial dissemination, development of symptoms, lung histology and monocyte subsets in blood and lungs. CCR2-deficient mice showed a delayed onset of disease and resolution of symptoms, higher concentrations and impaired clearance of bacteria in the lung and the liver, accompanied by a slow infiltration of interstitial macrophages into the lungs. In the blood, we found an induction of circulating monocytes that depended on CCR2, while only a small increase in Ly6C monocytes was observed in mice. In the lung, significantly higher numbers of Ly6C and Ly6C monocytes were found in the C57BL/6 mice compared to mice. Both wildtype and CCR2-deficient mice developed an inflammatory milieu as shown by cytokine and / mRNA induction in the lung, but with delayed kinetics in CCR2-deficient mice. Histopathology revealed that infiltration of macrophages to the parenchyma, but not into the peribronchial tissue, depended on CCR2. In sum, our data suggest that in infection, CCR2 drives blood monocytosis and the influx and activation of Ly6C and Ly6C monocytes into the lung, thereby accelerating bacterial replication and development of interstitial pulmonary inflammation.
Topics: Animals; Antigens, Ly; Bacterial Load; Chemotaxis, Leukocyte; Disease Models, Animal; Female; Host-Pathogen Interactions; Liver; Lung; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Orientia tsutsugamushi; Receptors, CCR2; Scrub Typhus; Mice
PubMed: 34290699
DOI: 10.3389/fimmu.2021.670219 -
Atherosclerosis Jul 2013Previous studies have shown that mice with defects in cellular cholesterol efflux show hematopoietic stem cell (HSPC) and myeloid proliferation, contributing to...
Previous studies have shown that mice with defects in cellular cholesterol efflux show hematopoietic stem cell (HSPC) and myeloid proliferation, contributing to atherogenesis. We hypothesized that the combination of hypercholesterolemia and defective cholesterol efflux would promote HSPC expansion and leukocytosis more prominently than either alone. We crossed Ldlr(-/-) with Apoa1(-/-) mice and found that compared to Ldlr(-/-) mice, Ldlr(-/-)/Apoa1(+/-) mice, with similar LDL-cholesterol levels but reduced HDL-cholesterol (HDL-C) levels, had expansion of HSPCs, monocytosis and neutrophilia. Ex vivo studies showed that HSPCs expressed high levels of Ldlr, Scarb1 (Srb1), and Lrp1 and were able to take up both native and oxidized LDL. Native LDL directly stimulated HSPC proliferation, while co-incubation with reconstituted HDL attenuated this effect. We also assessed the impact of HDL-C levels on monocytes in children with familial hypercholesterolemia (FH) (n = 49) and found that subjects with the lowest level of HDL-C, had increased monocyte counts compared to the mid and higher HDL-C levels. Overall, HDL-C was inversely correlated with the monocyte count. These data suggest that in mice, a balance of cholesterol uptake and efflux mechanisms may be one factor in driving HSPC proliferation and monocytosis. Higher monocyte counts in children with FH and low HDL-cholesterol suggest a similar pattern in humans.
Topics: Adolescent; Animals; Apolipoprotein A-I; Atherosclerosis; Cell Proliferation; Child; Cholesterol, HDL; Cholesterol, LDL; Female; Hematopoietic Stem Cells; Humans; Hyperlipoproteinemia Type II; Lipoproteins, LDL; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Neutrophils
PubMed: 23684512
DOI: 10.1016/j.atherosclerosis.2013.03.031