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Haematologica Dec 2009The World Health Organization classification of tumors of hematopoietic and lymphoid tissues includes within myeloid neoplasms the category...
The World Health Organization classification of tumors of hematopoietic and lymphoid tissues includes within myeloid neoplasms the category myelodysplastic/myeloproliferative neoplasms. In this perspective article Drs. Reiter, Invernizzi, Cross and Cazzola discuss our present knowledge of the molecular basis of these disorders. See related paper on page 1676.
Topics: DNA Mutational Analysis; DNA-Binding Proteins; Dioxygenases; Genetic Predisposition to Disease; Humans; Leukemia, Myelomonocytic, Chronic; Mutation; Myelodysplastic-Myeloproliferative Diseases; Proto-Oncogene Proteins
PubMed: 19996113
DOI: 10.3324/haematol.2009.014001 -
American Journal of Hematology Jun 2016Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by overlapping features of myelodysplastic syndromes and... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. Diagnosis is based on the presence of persistent (>3 months) peripheral blood monocytosis (>1 × 10(9) /L), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼20-30% of patients, while >90% have gene mutations. Mutations involving TET2 (∼60%), SRSF2 (∼50%), ASXL1 (∼40%), and RAS (∼30%) are frequent; with only ASXL1 mutations negatively impacting overall survival. Two molecularly integrated, CMML-specific prognostic models include; the Groupe Français des Myélodysplasies (GFM) and the Molecular Mayo Model (MMM). The GFM model segregates patients into 3 groups based on: age >65 years, WBC >15 × 10(9) /L, anemia, platelets <100 × 10(9) /L, and ASXL1 mutation status, with respective median survivals of 56 (low), 27.4 (intermediate), and 9.2 (high) months. The MMM is based on ASXL1 mutational status, absolute monocyte count >10 × 10(9) /L, hemoglobin <10 g/dL, platelets <100 × 109/L and circulating immature myeloid cells. This model stratifies patients into four 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. 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%. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality. Individualized therapy, including epigenetic modifiers and small molecule inhibitors, are exciting prospects. Am. J. Hematol. 91:632-642, 2016. © 2016 Wiley Periodicals, Inc.
Topics: Aged; Disease Management; Female; Humans; Leukemia, Myelomonocytic, Chronic; Male; Prognosis; Risk Assessment
PubMed: 27185207
DOI: 10.1002/ajh.24396 -
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 -
Haematologica Jan 2023
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Disease Progression
PubMed: 35443568
DOI: 10.3324/haematol.2022.280960 -
Haematologica Feb 2010
Topics: Child; Genes, ras; Humans; Janus Kinases; Leukemia, Myelomonocytic, Juvenile; Mutation; Neurofibromatosis 1; Neurofibromin 1; PTEN Phosphohydrolase; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins c-cbl; STAT Transcription Factors; Signal Transduction; ras Proteins
PubMed: 20139388
DOI: 10.3324/haematol.2009.016865 -
Cellular and Molecular Life Sciences :... Jun 2017Deficiency in cerebral amyloid β-protein (Aβ) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of... (Review)
Review
Deficiency in cerebral amyloid β-protein (Aβ) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of misfolded Aβ in the brain is believed to be a net result of imbalance between its production and removal. This in turn may trigger neuroinflammation, progressive synaptic loss, and ultimately cognitive decline. Clearance of cerebral Aβ is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Recent studies have highlighted a new, unexpected role for peripheral monocytes and macrophages in restricting cerebral Aβ fibrils, and possibly soluble oligomers. In AD transgenic (ADtg) mice, monocyte ablation or inhibition of their migration into the brain exacerbated Aβ pathology, while blood enrichment with monocytes and their increased recruitment to plaque lesion sites greatly diminished Aβ burden. Profound neuroprotective effects in ADtg mice were further achieved through increased cerebral recruitment of myelomonocytes overexpressing Aβ-degrading enzymes. This review summarizes the literature on cellular and molecular mechanisms of cerebral Aβ clearance with an emphasis on the role of peripheral monocytes and macrophages in Aβ removal.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Humans; Microglia; Monocytes; Proteolysis
PubMed: 28197669
DOI: 10.1007/s00018-017-2463-7 -
Journal of Advanced Research Jan 2024Leukocyte infiltration is an early event during cardiac remodeling frequently leading to heart failure (HF). Integrins mediate leukocyte infiltration during...
INTRODUCTION
Leukocyte infiltration is an early event during cardiac remodeling frequently leading to heart failure (HF). Integrins mediate leukocyte infiltration during inflammation. However, the importance of specific integrins in hypertensive cardiac remodeling is still unclear.
OBJECTIVES
To elucidate the significance of CD11b in hypertensive cardiac remodeling.
METHODS
Angiotensin (Ang II) or deoxycorticosterone acetate (DOCA)-salt was used to induce cardiac remodeling in mice of gene knockout (KO), bone marrow (BM) chimera, and the CD11b neutralizing antibody or agonist leukadherin-1 (LA1) treatment.
RESULTS
Our microarray data showed that integrin subunits Itgam (CD11b) and Itgb2 (CD18) were the most highly upregulated in Ang II-infused hearts. CD11b expression and CD11b/CD18 myelomonocytes were also time-dependently increased. KO or pharmacological blockade of CD11b greatly attenuated cardiac remodeling and macrophage infiltration and M1 polarization induced by Ang II or DOCA-salt. This protection was verified in wild-type mice transplanted with CD11b-deficient BM cells. Conversely, administration of CD11b agonist LA1 showed the opposite effects. Further, CD11b KO reduced Ang II-induced macrophage adhesion and M1 polarization, leading to reduction of cardiomyocyte enlargement and fibroblast differentiation in vitro. The numbers of CD14CD11bCD18 monocytes and CD15CD11bCD18 granulocytes were obviously higher in HF patients than in normal controls.
CONCLUSION
Our data demonstrate an important role of CD11b myeloid cells in hypertensive cardiac remodeling, and suggest that HF may benefit from targeting CD11b.
Topics: Humans; Animals; Mice; Ventricular Remodeling; Desoxycorticosterone Acetate; Macrophages; Hypertension; Heart Failure; Integrins
PubMed: 36822392
DOI: 10.1016/j.jare.2023.02.010 -
British Journal of Haematology Mar 2011Myeloid neoplasms derive from the pathological clonal expansion of an abnormal stem cell and span a diverse spectrum of phenotypes including acute myeloid leukaemia... (Review)
Review
Myeloid neoplasms derive from the pathological clonal expansion of an abnormal stem cell and span a diverse spectrum of phenotypes including acute myeloid leukaemia (AML), myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). Expansion of myeloid blasts with suppression of normal haematopoiesis is the hallmark of AML, whereas MPN is associated with over-proliferation of one or more lineages that retain the capacity to differentiate, and MDS is characterized by cytopenias and aberrant differentiation. MPD and MDS can progress to AML, which is likely due to the acquisition of cooperative mutations. Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap MPN/MDS by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukaemia, a similar disease in adults. While the current standard of care for patients with JMML relies on allogeneic haematopoietic stem cell transplant (HSCT), relapse is the most frequent cause of treatment failure. This review outlines our understanding of the genetic underpinnings of JMML with a recent update on the discovery of novel CBL mutations, as well as a brief review on current therapeutic approaches.
Topics: Animals; Antineoplastic Agents; Child; Disease Models, Animal; Genes, ras; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelomonocytic, Juvenile; Mice; Molecular Targeted Therapy; Neoplastic Syndromes, Hereditary; Prognosis
PubMed: 21623760
DOI: 10.1111/j.1365-2141.2010.08525.x -
Molecular Pathology : MP Jun 1997
Review
Topics: Antifungal Agents; Biomarkers; Body Fluids; Calcium-Binding Proteins; Gastrointestinal Diseases; Humans; Leukocyte L1 Antigen Complex; Monocytes; Neural Cell Adhesion Molecules; Rheumatic Diseases
PubMed: 9292145
DOI: 10.1136/mp.50.3.113 -
British Journal of Haematology Apr 2011The clinical, morphological, and genetic heterogeneity of chronic myelomonocytic leukaemia (CMML), has made it difficult to clearly assign this entity to a distinct... (Review)
Review
The clinical, morphological, and genetic heterogeneity of chronic myelomonocytic leukaemia (CMML), has made it difficult to clearly assign this entity to a distinct haematological category. In 2001, the World Health Organization transferred CMML to a new category of mixed myeloproliferative/myelodysplastic disorders, which was maintained in the last revision in 2008. Considering the rare occurrence of CMML, most pharmacotherapeutic and transplant studies combined CMML with myelodysplastic syndrome cases, but some clinical trials specifically investigated the use of demethylating agents in CMML and demonstrated stabilization of the haematological situation or even complete remission in subsets of patients. Information on the significance of other drugs is very limited. Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with CMML. Molecular studies revealed various novel genetic alterations in CMML - notably of the JAK2, TET2, CBL, IDH, or RUNX1 and RAS genes. This review summarizes the current status of pharmacotherapy and transplantation in CMML and outlines recent results of molecular research for diagnosis of this heterogeneous entity.
Topics: Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelomonocytic, Chronic; Male; Mutation; Neoplasm Proteins; Transplantation, Homologous
PubMed: 21401573
DOI: 10.1111/j.1365-2141.2011.08631.x