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American Journal of Hematology Apr 2023Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms...
DISEASE OVERVIEW
Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow.
DIAGNOSIS
aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN-NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), and aCML.
MUTATIONS AND KARYOTYPE
Cytogenetic abnormalities are seen in 40-50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN-NOS can be further stratified by mutational profiles into CMML-like, MDS/MPN-RS-T-like, aCML-like, TP35-mutated, and "others", respectively.
RISK STRATIFICATION
The Mayo Clinic aCML model stratifies patients based on age >67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low-risk (0-1 points) and high-risk (>2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN-NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS-R.
TREATMENT
Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality.
Topics: Humans; Aged; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Myelodysplastic Syndromes; Leukocytosis; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myelomonocytic, Chronic; Thrombocytosis; Mutation; Risk Assessment
PubMed: 36601682
DOI: 10.1002/ajh.26828 -
Blood Jun 2015Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/ myeloproliferative neoplasm whose diagnosis is currently based on the elevation of peripheral blood... (Clinical Trial)
Clinical Trial
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/ myeloproliferative neoplasm whose diagnosis is currently based on the elevation of peripheral blood monocytes to >1 × 10(9)/L, measured for ≥3 months. Diagnosis can be ambiguous; for example, with prefibrotic myelofibrosis or reactive monocytosis. We set up a multiparameter flow cytometry assay to distinguish CD14(+)/CD16(-) classical from CD14(+)/CD16(+) intermediate and CD14(low)/CD16(+) nonclassical monocyte subsets in peripheral blood mononucleated cells and in total blood samples. Compared with healthy donors and patients with reactive monocytosis or another hematologic malignancy, CMML patients demonstrate a characteristic increase in the fraction of CD14(+)/CD16(-) cells (cutoff value, 94.0%). The associated specificity and sensitivity values were 95.1% and 90.6% in the learning cohort (175 samples) and 94.1% and 91.9% in the validation cohort (307 samples), respectively. The accumulation of classical monocytes, which demonstrate a distinct gene expression pattern, is independent of the mutational background. Importantly, this increase disappears in patients who respond to hypomethylating agents. We conclude that an increase in the fraction of classical monocytes to >94.0% of total monocytes is a highly sensitive and specific diagnostic marker that rapidly and accurately distinguishes CMML from confounding diagnoses.
Topics: Aged; Aged, 80 and over; Female; Flow Cytometry; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lipopolysaccharide Receptors; Male; Middle Aged; Monocytes; Receptors, IgG; Sensitivity and Specificity
PubMed: 25852055
DOI: 10.1182/blood-2015-01-620781 -
Journal of Cellular and Molecular... Mar 2018Monocytosis and neutrophilia are frequent events in atherosclerosis. These phenomena arise from the increased proliferation of hematopoietic stem and multipotential... (Review)
Review
Monocytosis and neutrophilia are frequent events in atherosclerosis. These phenomena arise from the increased proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) and HSPC mobilization from the bone marrow to other immune organs and circulation. High cholesterol and inflammatory signals promote HSPC proliferation and preferential differentiation to the myeloid precursors (i.e., myelopoiesis) that than give rise to pro-inflammatory immune cells. These cells accumulate in the plaques thereby enhancing vascular inflammation and contributing to further lesion progression. Studies in animal models of atherosclerosis showed that manipulation with HSPC proliferation and differentiation through the activation of LXR-dependent mechanisms and restoration of cholesterol efflux may have a significant therapeutic potential.
Topics: Animals; Atherosclerosis; Bone Marrow; Cell Differentiation; Cell Proliferation; Cholesterol; Disease Models, Animal; Gene Expression Regulation; Hematopoietic Stem Cells; Humans; Hypercholesterolemia; Liver X Receptors; Mice; Monocytes; Multipotent Stem Cells; Neutrophils; Nuclear Receptor Subfamily 4, Group A, Member 1; Plaque, Atherosclerotic
PubMed: 29364567
DOI: 10.1111/jcmm.13462 -
American Journal of Hematology Apr 2022Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow...
DISEASE OVERVIEW
Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The 2013 seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL not only established its molecular pathogenesis but provided a diagnostic biomarker and rationale for pharmacological targeting.
DIAGNOSIS
In 2016, the World Health Organization (WHO) recognized activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 10 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.
MANAGEMENT
There is currently no standard of care for management of CNL, due in large part to the rarity of disease and dearth of formal clinical trials. Most commonly used therapeutic agents include conventional oral chemotherapy (e.g., hydroxyurea), interferon, and Janus kinase (JAK) inhibitors, while hematopoietic stem cell transplant remains the only potentially curative modality.
DISEASE UPDATES
Increasingly comprehensive genetic profiling in CNL, including new data on clonal evolution, has disclosed a complex genomic landscape with additional mutations and combinations thereof driving disease progression and drug resistance. Although accurate prognostic stratification and therapeutic decision-making remain challenging in CNL, emerging data on molecular biomarkers and the addition of newer agents, such as JAK inhibitors, to the therapeutic arsenal, are paving the way toward greater standardization and improvement of patient care.
Topics: Genomics; Humans; Leukemia, Neutrophilic, Chronic; Leukocytosis; Mutation; Prognosis
PubMed: 35089603
DOI: 10.1002/ajh.26481 -
Blood Advances Jul 2022Monocytosis may occur in numerous inflammatory conditions but is also the defining feature of chronic myelomonocytic leukemia (CMML). Clonal somatic mutations detectable...
Monocytosis may occur in numerous inflammatory conditions but is also the defining feature of chronic myelomonocytic leukemia (CMML). Clonal somatic mutations detectable in CMML may occur with aging in otherwise healthy individuals, so-called "clonal hematopoiesis" (CH). We investigated whether the combination of CH and monocytosis would represent an early developmental stage of CMML. We studied community-dwelling individuals with monocytosis (≥1 × 109/L and ≥10% of leukocytes) in the population-based Lifelines cohort (n = 144 676 adults). The prevalence and spectrum of CH were evaluated for individuals ≥60 years with monocytosis (n = 167 [0.8%]), and control subjects 1:3 matched for age and sex (n = 501). Diagnoses of hematological malignancies were retrieved by linkage to the Netherlands Cancer Registry (NCR). Monocyte counts and the prevalence of monocytosis increased with advancing age. Older individuals with monocytosis more frequently carried CH (50.9% vs 35.5%; P < .001). Monocytosis is associated with enrichment of multiple gene mutations (P = .006) and spliceosome mutations (P = .007) but not isolated mutated DNMT3A, TET2, or ASXL1. Persistent monocytosis over 4 years was observed in 30/102 evaluable individuals and associated with a higher prevalence of CH (63%). Myeloid malignancies, including 1 case of CMML, developed in 4 individuals with monocytosis who all carried CH. In conclusion, monocytosis and CH both occur at an older age and do not necessarily reflect clonal monocytic proliferation. In a fraction of older subjects with monocytosis, CH might constitute early clonal dominance in developing malignant myelomonocytic disease. Mutational spectra deviating from age-related CH require attention.
Topics: Adult; Clonal Hematopoiesis; Humans; Independent Living; Leukemia, Myelomonocytic, Chronic; Leukocytosis; Mutation; Myeloproliferative Disorders
PubMed: 35561316
DOI: 10.1182/bloodadvances.2021006755 -
Immunological Reviews Nov 2014Monocytes are part of the vertebrate innate immune system. Blood monocytes are produced by bone marrow and splenic progenitors that derive from hematopoietic stem cells... (Review)
Review
Monocytes are part of the vertebrate innate immune system. Blood monocytes are produced by bone marrow and splenic progenitors that derive from hematopoietic stem cells (HSCs). In cardiovascular disease, such as atherosclerosis and myocardial infarction, HSCs proliferate at higher levels that in turn increase production of hematopoietic cells, including monocytes. Once produced in hematopoietic niches, monocytes intravasate blood vessels, circulate, and migrate to sites of inflammation. Monocyte recruitment to atherosclerotic plaque and the ischemic heart depends on various chemokines, such as CCL2, CX3 CL1, and CCL5. Once in tissue, monocytes can differentiate into macrophages and dendritic cells. Macrophages are end effector cells that regulate the steady state and tissue healing, but they can also promote disease. At sites of inflammation, monocytes and macrophages produce inflammatory cytokines, which can exacerbate disease progression. Macrophages can also phagocytose tissue debris and produce pro-healing cytokines. Additionally, macrophages are antigen-presenting cells and can prime T cells. The tissue environment, including cytokines and types of inflammation, instructs macrophage specialization. Understanding monocytosis and its consequences in disease will reveal new therapeutic opportunities without compromising steady state functions.
Topics: Animals; Cardiovascular Diseases; Cell Differentiation; Cell Movement; Hematopoietic Stem Cells; Humans; Inflammation; Leukocytosis; Macrophages; Monocytes; Myeloid Progenitor Cells; Myelopoiesis; Organ Specificity
PubMed: 25319334
DOI: 10.1111/imr.12219 -
Orphanet Journal of Rare Diseases Feb 2013First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth... (Review)
Review
First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.
Topics: Barth Syndrome; Heart Diseases; Humans; Male
PubMed: 23398819
DOI: 10.1186/1750-1172-8-23 -
JCI Insight Sep 2022Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase...
Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet-fed (WD-fed) Ldlr-/- mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.
Topics: Aminopyridines; Animals; Atherosclerosis; Bile Acids and Salts; Diabetes Mellitus, Experimental; Humans; Hypercholesterolemia; I-kappa B Kinase; Mice; Protein Serine-Threonine Kinases
PubMed: 35917178
DOI: 10.1172/jci.insight.155552 -
Current Hematologic Malignancy Reports Jun 2021Monocytosis is a frequently encountered clinical condition that needs appropriate investigation due to a broad range of differential diagnoses. This review is meant to... (Review)
Review
PURPOSE OF REVIEW
Monocytosis is a frequently encountered clinical condition that needs appropriate investigation due to a broad range of differential diagnoses. This review is meant to summarize the latest literature in the diagnostic testing and interpretation and offer a stepwise diagnostic approach for a patient presenting with monocytosis.
RECENT FINDINGS
Basic studies have highlighted the phenotypic and functional heterogeneity in the monocyte compartment. Studies, both translational and clinical, have provided insights into why monocytosis occurs and how to distinguish the different etiologies. Flow cytometry studies have illustrated that monocyte repartitioning can distinguish chronic myelomonocytic leukemia, a prototypical neoplasm with monocytosis from other reactive or neoplastic causes. In summary, we provide an algorithmic approach to the diagnosis of a patient presenting with monocytosis and expect this document to serve as a reference guide for clinicians.
Topics: Biomarkers, Tumor; Bone Marrow; Clonal Evolution; Diagnosis, Differential; Disease Management; Disease Susceptibility; Flow Cytometry; Humans; Leukemia, Myeloid; Leukemia, Myelomonocytic, Chronic
PubMed: 33880680
DOI: 10.1007/s11899-021-00618-4 -
Trends in Endocrinology and Metabolism:... Mar 2013Atherosclerosis is characterized by the progressive accumulation of lipids and leukocytes in the arterial wall. Leukocytes such as macrophages accumulate oxidized... (Review)
Review
Atherosclerosis is characterized by the progressive accumulation of lipids and leukocytes in the arterial wall. Leukocytes such as macrophages accumulate oxidized lipoproteins in the growing atheromata and give rise to foam cells, which can then contribute to the necrotic core of lesions. Lipids and leukocytes also interact in other important ways. In experimental models, systemic hypercholesterolemia is associated with severe neutrophilia and monocytosis. Recent evidence indicates that cholesterol-sensing pathways control the proliferation of hematopoietic stem-cell progenitors. Here we review some of the studies that are forging this particular link between metabolism and inflammation, and propose several strategies that could target this axis for the treatment of cardiovascular disease.
Topics: Animals; Atherosclerosis; Foam Cells; Hematopoiesis; Hematopoietic Stem Cells; Humans; Hypercholesterolemia; Inflammation; Liver X Receptors; Monocytes; Orphan Nuclear Receptors
PubMed: 23228326
DOI: 10.1016/j.tem.2012.10.008