-
Circulation Research Sep 2020Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation....
RATIONALE
Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear.
OBJECTIVE
To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis.
METHODS AND RESULTS
To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C subset, and neutrophils. Hematopoietic-restricted deletion of , , or its cognate receptor prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis.
CONCLUSIONS
Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.
Topics: Animals; Atherosclerosis; Biomarkers; Blood Glucose; Calgranulin A; Calgranulin B; Diet, High-Fat; Disease Models, Animal; Glucose Transporter Type 1; Glycolysis; Hyperglycemia; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Monocytes; Myelopoiesis; Neutrophils; Plaque, Atherosclerotic; Receptor for Advanced Glycation End Products; Signal Transduction
PubMed: 32564710
DOI: 10.1161/CIRCRESAHA.120.316653 -
Blood Jul 2017Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 10/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 10/L) and proliferative (white blood cell count ≥13 × 10/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient's quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.
Topics: Adult; Aged; Aged, 80 and over; Aging; Antineoplastic Agents; Cell Proliferation; Clinical Decision-Making; Cytotoxins; Disease Management; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Monocytes; Quality of Life; Transplantation, Homologous
PubMed: 28572287
DOI: 10.1182/blood-2017-04-736421 -
Leukemia Sep 2023In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78;...
In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 10/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 10/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.
Topics: Humans; Receptor, Platelet-Derived Growth Factor beta; Receptor, Platelet-Derived Growth Factor alpha; Oncogene Proteins, Fusion; Myeloproliferative Disorders; Eosinophilia; Lymphoma; Gene Fusion
PubMed: 37454239
DOI: 10.1038/s41375-023-01958-1 -
The American Journal of the Medical... Mar 2017Mast cell activation syndrome (MCAS), a recently recognized nonneoplastic mast cell disease driving chronic multisystem inflammation and allergy, appears prevalent and...
BACKGROUND
Mast cell activation syndrome (MCAS), a recently recognized nonneoplastic mast cell disease driving chronic multisystem inflammation and allergy, appears prevalent and thus important. We report the first systematic characterization of a large MCAS population.
METHOD
Demographics, comorbidities, symptoms, family histories, physical examination and laboratory findings were reviewed in 298 retrospective and 115 prospective patients with MCAS. Blood samples from prospective subjects were examined by flow cytometry for clonal mast cell disease and tested for cytokines potentially driving the monocytosis frequent in MCAS.
RESULTS
Demographically, white females dominated. Median ages at symptom onset and diagnosis were 9 and 49 years, respectively (range: 0-88 and 16-92, respectively) and median time from symptom onset to diagnosis was 30 years (range: 1-85). Median numbers of comorbidities, symptoms, and family medical issues were 11, 20, and 4, respectively (range: 1-66, 2-84, and 0-33, respectively). Gastroesophageal reflux, fatigue and dermatographism were the most common comorbidity, symptom and examination finding. Abnormalities in routine laboratories were common and diverse but typically modest. The most useful diagnostic markers were heparin, prostaglandin D, histamine and chromogranin A. Flow cytometric and cytokine assessments were unhelpful.
CONCLUSIONS
Our study highlights MCAS׳s morbidity burden and challenging heterogeneity. Recognition is important given good survival and treatment prospects.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Child; Child, Preschool; Chromogranin A; Female; Heparin; Histamine; Humans; Infant; Infant, Newborn; Male; Mastocytosis; Middle Aged; Prospective Studies; Prostaglandin D2; Retrospective Studies; Syndrome; Young Adult
PubMed: 28262205
DOI: 10.1016/j.amjms.2016.12.013 -
Microorganisms Jan 2021is classified as a relapsing fever spirochete. Although is genetically and ecologically distinct from sensu lato, both microorganisms are transmitted by the same... (Review)
Review
is classified as a relapsing fever spirochete. Although is genetically and ecologically distinct from sensu lato, both microorganisms are transmitted by the same tick species. was detected in ticks in 1994 in Japan. A phylogenetic analysis based on selected sequences of genome revealed genetic differences between isolates from Asia, North America, and Europe, which are clearly separated into three genotypes. Symptomatic human cases of disease (BMD) were first reported in 2011 in Russia and then in North America, Europe, and Asia. The most common clinical manifestation of BMD is fever with flu-like symptoms. Several differences in rare symptoms (thrombocytopenia, monocytosis, cerebrospinal fluid pleocytosis, or symptoms related to the central nervous system) have been noted among cases caused by Asian, European, and American types of . BMD should be considered in the diagnosis of patients after tick bites, particularly with meningoencephalitis, without anti- antibodies in the cerebrospinal fluid. This review describes the biology, ecology, and potential of as a tick-borne pathogen of public health concern, with particular emphasis on Europe.
PubMed: 33445492
DOI: 10.3390/microorganisms9010154 -
Indian Journal of Hematology & Blood... Sep 2013Juvenile myelomonocytic leukemia (JMML) is a rare fatal hematopoietic disorder of early childhood. We are presenting a case of 9-month-old female child who was admitted...
Juvenile myelomonocytic leukemia (JMML) is a rare fatal hematopoietic disorder of early childhood. We are presenting a case of 9-month-old female child who was admitted with abdominal distension, irritability, and hepatosplenomegaly. Peripheral blood film examination showed leukoerythroblastosis with leukocytosis, absolute monocytosis, microcytic hypo chromic anemia, and thrombocytopenia. Bone marrow examination showed myeloid hyperplasia, Hb HPLC revealed normal HbF (1.3 %) and HbA2 (2.9 %). There was absolute gamma globulinemia and DCT positivity. Cytogenetic studies revealed a normal karyotype with absence of Philadelphia (Ph) chromosome, monosomy 7 or any other chromosomal abnormality. Diagnosis of JMML was rendered according to the diagnostic criteria laid down by WHO classification 2008 with presence of peripheral blood monocytosis >1 × 10(9)/L, blasts <20 % of leucocytes in blood or nucleated cells in bone marrow, absence of Ph chromosome, presence of immature granulocytes in the blood and WBC count >10 × 10(9)/L. The patient was then started on a regimen of chemotherapy to which she gave a promising response.
PubMed: 24426365
DOI: 10.1007/s12288-012-0164-9 -
Scientific Reports Oct 2020Bone marrow erythropoiesis is mainly homeostatic and a demand of oxygen in tissues activates stress erythropoiesis in the spleen. Here, we show an increase in the number...
Bone marrow erythropoiesis is mainly homeostatic and a demand of oxygen in tissues activates stress erythropoiesis in the spleen. Here, we show an increase in the number of circulating erythrocytes in apolipoprotein E mice fed a Western high-fat diet, with similar number of circulating leukocytes and CD41 events (platelets). Atherogenic conditions increase spleen erythropoiesis with no variations of this cell lineage in the bone marrow. Spleens from atherogenic mice show augmented number of late-stage erythroblasts and biased differentiation of progenitor cells towards the erythroid cell lineage, with an increase of CD71CD41CD34CD117Sca1Lin cells (erythroid-primed megakaryocyte-erythroid progenitors), which is consistent with the way in which atherogenesis modifies the expression of pro-erythroid and pro-megakaryocytic genes in megakaryocyte-erythroid progenitors. These data explain the transiently improved response to an acute severe hemolytic anemia insult found in atherogenic mice in comparison to control mice, as well as the higher burst-forming unit-erythroid and colony forming unit-erythroid capacity of splenocytes from atherogenic mice. In conclusion, our work demonstrates that, along with the well stablished enhancement of monocytosis during atherogenesis, stress erythropoiesis in apolipoprotein E mice fed a Western high fat diet results in increased numbers of circulating red blood cells.
Topics: Animals; Antigens, CD; Atherosclerosis; Cell Differentiation; Erythroid Precursor Cells; Erythropoiesis; Hematopoiesis, Extramedullary; Mice; Mice, Knockout, ApoE; Spleen; Stress, Physiological
PubMed: 33116141
DOI: 10.1038/s41598-020-74665-x -
Blood Mar 2024The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the...
The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the definition of chronic myelomonocytic leukemia (CMML). To assess its qualitative and quantitative implications for patient care, we started with 3311 established CMML cases (according to WHO 2017 criteria) and included 2130 oligomonocytosis cases fulfilling the new CMML diagnostic criteria. Applying both 2022 classification systems, 356 and 241 of oligomonocytosis cases were newly classified as myelodysplastic (MD)-CMML (WHO and ICC 2022, respectively), most of which were diagnosed as myelodysplastic syndrome (MDS) according to the WHO 2017 classification. Importantly, 1.5 times more oligomonocytosis cases were classified as CMML according to WHO 2022 than based on ICC, because of different diagnostic criteria. Genetic analyses of the newly classified CMML cases showed a distinct mutational profile with strong enrichment of MDS-typical alterations, resulting in a transcriptional subgroup separated from established MD and myeloproliferative CMML. Despite a different cytogenetic, molecular, immunophenotypic, and transcriptional landscape, no differences in overall survival were found between newly classified and established MD-CMML cases. To the best of our knowledge, this study represents the most comprehensive analysis of routine CMML cases to date, both in terms of clinical characterization and transcriptomic analysis, placing newly classified CMML cases on a disease continuum between MDS and previously established CMML.
Topics: Humans; Consensus; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukocytosis; World Health Organization; Prognosis; Organic Chemicals
PubMed: 38064663
DOI: 10.1182/blood.2023021199 -
British Journal of Haematology May 2014Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap features, and an inherent... (Review)
Review
Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap features, and an inherent tendency to transform to acute myeloid leukaemia. Approximately 30% of patients present with clonal cytogenetic abnormalities, while almost 90% have molecular aberrations involving epigenetic regulation, the spliceosome component machinery, tumour suppressor genes and transcription factors/regulators. Numerous prognostic models exist for CMML, with more recent models incorporating prognostic mutations, such as those involving ASXL1. Other variables that seem to consistently affect outcomes include the degree of leucocytosis/monocytosis, anaemia and thrombocytopenia. Allogeneic stem cell transplant remains the only curative option for CMML, while hypomethylating agents can be used for transplant-ineligible patients or those without suitable stem cell sources. Targeting biological pathways activated in CMML offers potential hope for more effective and less toxic therapies.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Prognosis; Stem Cell Transplantation; Transplantation, Homologous
PubMed: 24467717
DOI: 10.1111/bjh.12756 -
The Oncologist May 2021Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features including myeloid hyperplasia, splenomegaly, and constitutional symptoms. Because of vast clinical heterogeneity in presentation and course, risk stratification is used for a risk-adapted treatment strategy. Numerous prognostic scoring systems exist, some of which incorporate mutational information. Treatment ranges from observation to allogeneic hematopoietic stem cell transplantation. Therapies include hydroxyurea for cytoreduction, hypomethylating agents, and the JAK1/2 inhibitor ruxolitinib to address splenomegaly and constitutional symptoms. Recently, oral decitabine with cedazuridine was approved and represents a convenient treatment option for CMML patients. Although novel therapeutics are in development for CMML, further work is needed to elucidate possible targets unique to the CMML clone. In this review, we will detail the pathophysiology, risk stratification, available treatment modalities, and novel therapies for CMML, and propose a modern treatment algorithm. IMPLICATIONS FOR PRACTICE: Chronic myelomonocytic leukemia (CMML) is a clinically heterogenous disease, which poses significant management challenges. The diagnosis of CMML requires bone marrow biopsy and aspirate with thorough evaluation. Risk stratification and symptom assessment are essential to designing an effective treatment plan, which may include hypomethylating agents (HMAs) in intermediate or high-risk patients. The recently approved oral decitabine/cedazuridine provides a convenient alternative to parenteral HMAs. Ruxolitinib may be effective in ameliorating proliferative symptoms and splenomegaly. Allogeneic stem cell transplantation remains the only treatment with curative potential; however, novel therapies are in clinical development which may significantly alter the therapeutic landscape of CMML.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Leukemia, Myelomonocytic, Chronic; Mutation; Risk Assessment
PubMed: 33792103
DOI: 10.1002/onco.13769