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Journal of Internal Medicine May 2021Haematopoietic stem and progenitor cells (HSPCs) are defined as unspecialized cells that give rise to more differentiated cells. In a similar way, leukaemic stem and... (Review)
Review
Haematopoietic stem and progenitor cells (HSPCs) are defined as unspecialized cells that give rise to more differentiated cells. In a similar way, leukaemic stem and progenitor cells (LSPCs) are defined as unspecialized leukaemic cells, which can give rise to more differentiated cells. Leukaemic cells carry leukaemic mutations/variants and have clear differentiation abnormalities. Pre-leukaemic HSPCs (PreL-HSPCs) carry pre-leukaemic mutations/variants (pLMs) and are capable of producing mature functional cells, which will carry the same variants. Under the roof of LSPCs, one can find a broad range of cell types genetic and disease phenotypes. Present-day knowledge suggests that this phenotypic heterogeneity is the result of interactions between the cell of origin, the genetic background and the microenvironment background. The combination of these attributes will define the LSPC phenotype, frequency, differentiation capacity and evolutionary trajectory. Importantly, as LSPCs are leukaemia-initiating cells that sustain clinical remission and are the source of relapse, an improved understanding of LSPCs phenotype would offer better clinical opportunities for the treatment and hopefully prevention of human leukaemia. The current review will focus on LSPCs attributes in the context of human haematologic malignancies.
Topics: Biomarkers, Tumor; Bone Marrow; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genetic Variation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukemia; Mutation; Phenotype; Preleukemia; Tumor Microenvironment
PubMed: 33511694
DOI: 10.1111/joim.13236 -
Journal of Biomedicine & Biotechnology 2011Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid... (Review)
Review
Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs) are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs) are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia.
Topics: Adolescent; Animals; Child; Clinical Trials as Topic; Drug Evaluation, Preclinical; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Leukemia
PubMed: 21318168
DOI: 10.1155/2011/148046 -
Biochimica Et Biophysica Acta Jan 2015Macroautophagy, usually referred to as autophagy, is a degradative pathway wherein cytoplasmatic components such as aggregated/misfolded proteins and organelles are... (Review)
Review
Macroautophagy, usually referred to as autophagy, is a degradative pathway wherein cytoplasmatic components such as aggregated/misfolded proteins and organelles are engulfed within double-membrane vesicles (autophagosomes) and then delivered to lysosomes for degradation. Autophagy plays an important role in the regulation of numerous physiological functions, including hematopoiesis, through elimination of aggregated/misfolded proteins, and damaged/superfluous organelles. The catabolic products of autophagy (amino acids, fatty acids, nucleotides) are released into the cytosol from autophagolysosomes and recycled into bio-energetic pathways. Therefore, autophagy allows cells to survive starvation and other unfavorable conditions, including hypoxia, heat shock, and microbial pathogens. Nevertheless, depending upon the cell context and functional status, autophagy can also serve as a death mechanism. The cohort of proteins that constitute the autophagy machinery function in a complex, multistep biochemical pathway which has been partially identified over the past decade. Dysregulation of autophagy may contribute to the development of several disorders, including acute leukemias. In this kind of hematologic malignancies, autophagy can either act as a chemo-resistance mechanism or have tumor suppressive functions, depending on the context. Therefore, strategies exploiting autophagy, either for activating or inhibiting it, could find a broad application for innovative treatment of acute leukemias and could significantly contribute to improved clinical outcomes. These aspects are discussed here after a brief introduction to the autophagic molecular machinery and its roles in hematopoiesis.
Topics: Acute Disease; Autophagy; Hematopoiesis; Humans; Leukemia; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 25284725
DOI: 10.1016/j.bbamcr.2014.09.023 -
Einstein (Sao Paulo, Brazil) 2023To characterize the immunophenotypic profile of acute leukemias in the population of the state of Bahia, Brazil.
OBJECTIVE
To characterize the immunophenotypic profile of acute leukemias in the population of the state of Bahia, Brazil.
METHODS
This is a descriptive, retrospective study. From 2014 to 2018, 796 new cases of acute leukemia were evaluated. The data were obtained from analysis of reports and records of tests performed by flow cytometry immunophenotyping. All individuals of all age groups diagnosed as acute lymphoblastic leukemia or acute myeloid leukemia were included in the study. Demographic variables and expression of leukemia antigens were evaluated.
RESULTS
Most cases were diagnosed as acute myeloid leukemia and 42.7% as acute lymphoblastic leukemia. Significant differences were found in expression of markers in acute leukemias when age groups were compared, as well as in demographic characteristics. B-cell acute lymphoblastic leukemia was more prevalent than cases of T-cell origin. Assessing the aberrant markers in acute myeloid leukemias, the non-acute promyelocytic leukemia group presented expression of CD7 and CD56 as the most frequent ones. In B-cell acute lymphoblastic leukemia, the most frequent aberrant markers were CD66c, CD13 and CD33.
CONCLUSION
Significant differences were found as to several antigens when comparing adults and children, and these findings may contribute to future studies correlating the phenotypic profile to genetic characteristics and therapeutic response, including specific antigen therapies, which may be better targeted.
Topics: Child; Adult; Humans; Brazil; Retrospective Studies; Immunophenotyping; Leukemia, Myeloid, Acute; Acute Disease; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Flow Cytometry
PubMed: 36629681
DOI: 10.31744/einstein_journal/2023AO0117 -
British Journal of Haematology Mar 2018Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major... (Review)
Review
Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches.
Topics: Humans; Leukemia, Myelomonocytic, Acute; Leukemia, T-Cell; Myeloid Cells; Neoplasm Proteins; Precursor Cells, T-Lymphoid
PubMed: 29441563
DOI: 10.1111/bjh.15129 -
Journal of Clinical Pathology Feb 1985This report summarises the current knowledge regarding the clinical utility of biochemical enzyme markers for both diagnostic and therapeutic purposes in acute... (Review)
Review
This report summarises the current knowledge regarding the clinical utility of biochemical enzyme markers for both diagnostic and therapeutic purposes in acute leukaemia. The enzymes studied most extensively in this field are terminal deoxynucleotidyl transferase, adenosine deaminase, 5'-nucleotidase, purine nucleoside phosphorylase, and acid phosphatase, esterase, hexosaminidase isoenzymes. For each enzyme, the quantitative and qualitative characteristics in various immunologically defined subclasses of acute leukaemia are described. The quantitative evaluation of enzyme activities represents an adjunctive classification technique which should be incorporated into the multivariate analysis, the "multiple marker analysis." By qualitative characterisation pronounced heterogeneity of leukaemia subsets is uncovered. The application of 2'-deoxycoformycin, a specific inhibitor of adenosine deaminase, and the potential usefulness of two other enzymes as targets for treatment with selective agents is discussed. The concept that gene products expressed at certain developmental stages of normal cells can similarly be detected in leukaemic cells (which therefore seem to be "frozen" or "arrested" at this particular maturation/differentiation stage) is supported by the results obtained in enzyme studies. Besides their practical clinical importance for classification and treatment of acute leukaemias, biochemical enzyme markers constitute a valuable research tool to disclose biological properties of leukaemic cells.
Topics: 5'-Nucleotidase; Acid Phosphatase; Acute Disease; Adenosine Deaminase; DNA Nucleotidylexotransferase; Enzyme Inhibitors; Esterases; Hexosaminidases; Humans; Leukemia; Leukocytes; Nucleotidases; Phenotype; Purine-Nucleoside Phosphorylase
PubMed: 2981904
DOI: 10.1136/jcp.38.2.117 -
Cancer Imaging : the Official... Feb 2013Acute leukaemias are relatively common malignancies. Treatment has advanced significantly in the recent past and there has been improved patient survival. This improved... (Review)
Review
Acute leukaemias are relatively common malignancies. Treatment has advanced significantly in the recent past and there has been improved patient survival. This improved initial response is leading to an increasing number of cases of relapse. Extramedullary relapse occurs in a wide variety of locations with varying presentations, imaging findings and differentials. The pathophysiology and clinical course of recurrent extramedullary myeloid and lymphocytic leukaemias are reviewed in this article. The wide variety of imaging findings associated with many important sites of recurrence and the associated differential diagnosis are discussed and illustrated.
Topics: Diagnosis, Differential; Female; Humans; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Tomography, X-Ray Computed
PubMed: 23439108
DOI: 10.1102/1470-7330.2013.0004 -
Revista de Investigacion Clinica;... 2021In this article, the perspectives on both the diagnosis and treatment of acute leukemias, chronic leukemias, multiple myeloma, anemia, platelet, and coagulation...
In this article, the perspectives on both the diagnosis and treatment of acute leukemias, chronic leukemias, multiple myeloma, anemia, platelet, and coagulation disorders are briefly discussed. We emphasize the limitations facing the practice of hematology in low- and middle-income countries.
Topics: Anemia; Blood Coagulation Disorders; Hematology; Humans; Leukemia; Multiple Myeloma
PubMed: 34609367
DOI: 10.24875/RIC.21000292 -
British Journal of Haematology Jan 2020Acute myeloid leukaemia (AML) is a blood cancer characterized by acquired genetic mutations. There is great interest in accurately establishing measurable residual... (Review)
Review
Acute myeloid leukaemia (AML) is a blood cancer characterized by acquired genetic mutations. There is great interest in accurately establishing measurable residual disease (MRD) burden in AML patients in remission after treatment but at risk of relapse. However, inter- and intrapatient genetic diversity means that, unlike in the chronic myeloid and acute promyelocytic leukaemias, no single genetic abnormality is pathognomonic for all cases of AML MRD. Next-generation sequencing offers the opportunity to test broadly and deeply for potential genetic evidence of residual AML, and while not currently accepted for such use clinically, is likely to be increasingly used for AML MRD testing in the future.
Topics: Hematologic Neoplasms; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Neoplasm, Residual
PubMed: 31804716
DOI: 10.1111/bjh.16362 -
Nature Reviews. Cancer Jan 2010Acute leukaemias are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis. It is now evident that epigenetic... (Review)
Review
Acute leukaemias are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis. It is now evident that epigenetic modifications, including DNA methylation and histone modifications, substantially contribute to the phenotype of leukaemia cells. An additional layer of epigenetic complexity is the pathogenetic role of microRNAs in leukaemias, and their key role in the transcriptional regulation of tumour suppressor genes and oncogenes. The genetic heterogeneity of acute leukaemias poses therapeutic challenges, but pharmacological agents that target components of the epigenetic machinery are promising as a component of the therapeutic arsenal for this group of diseases.
Topics: Animals; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Leukemia; MicroRNAs; Mutation
PubMed: 20029422
DOI: 10.1038/nrc2765