Constitutive Host Resistance
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
The mononuclear and polymorphonuclear phagocytes are produced in the bone marrow from a common stem cell (Figure 3.3). The stem cells committed to produce polymorphonuclear leukocytes differentiate into myeloblasts, and those that will produce mononuclear phagocytes differentiate into monoblasts. The sequence for polymorphonuclear leukocyte differentiation requires four cell divisions; each results in a progressive decrease in cell size and an increase in nuclear compaction. The compact nucleus ultimately assumes the characteristic polymorphonudear shape. The myeloblast gives rise to promyelocytes that divide to produce first myelocyte I cells, then myelocyte II cells. The myelocyte II cells give rise to metamyelocytes. Following the production of the metamyelocyte, no further cell division occurs. The metamyelocytes develop into band cells that become segmented cells and, finally, mature polymorphonuclear leukocytes as they leave the bone marrow and enter the blood. Under conditions of stress, such as is caused by infection, immature forms such as band cells may enter the blood.
Phagocytosis By Human Neutrophils
Hans H. Gadebusch in Phagocytes and Cellular Immunity, 2020
The maturation sequence of the neutrophil is outlined in Table 3. The neutrophil is derived from the bone marrow, probably from a pluripotent stem cell, that to this day has not been identified with certainty.17,18 The earliest morphologically distinct neutrophil precursor is the myeloblast, which has a large nucleus and very little cytoplasm. Granules begin to appear in the next, or promyelocyte stage, and are very obvious in the myelocytes. These granules are referred to as the primary (because they are the first to appear during development) or azurophil (because of their histochemical-staining characteristics) granules. They arise from the concave side of the Golgi apparatus, are relatively large in size (approximately 800 nm in diameter), and are electron dense.19 These granules contain the cell’s complement of myeloperoxidase, various acid hydrolases (including acid phosphatase and β-glucuronidase), a portion of the lysozyme, numerous cationic proteins, and various other components.20-23 When the cell is fully mature, the azurophil granules will make up only 10 to 20% of the total granule population of the cell.19
The Primer Hypothesis for the Regulation of Eukaryotic Gene Expression
M. Gerald, M.D. Kolodny in Eukaryotic Gene Regulation, 2018
Following exposure of fluorograms for 5 days, the thin layer chromatograms of the in vitro 3H-labeled alkaline hydrolysates of chicken erythrocyte DNA were compared with fluorograms of myeloblast tRNA. The qualitative and quantitative results of the major and minor bases of myeloblast tRNA were identical to those values previously reported.31 This assured us that the 3H-derivative method had been carried out correctly. In comparison, the fluorograms of the alkaline hydrolysate of chicken erythrocyte DNA revealed no spots for U′, A′, C, or G (the trialcohols, respectively, of uridine, adenosine, cytidine, and guanosine). Since the darkening of the film depends on the radioactivity of a spot, which in turn is directly proportional to the frequency of the particular base in the RNA, it was evident from the fluorograms that chicken erythrocytes contained no RNA associated with the CsCl-banded DNA within the limits of the sensitivity of the method that was used. While the lower limit of the method depends upon the specific activity of 3H-borohydride used, the 2 Ci/nmol preparation used, according to Randerath et al.,32 allowed us to assay for amounts of RNA as low as 0.1 pmol. Thus, this method should have been able to detect one base in a chain of 100,000 nucleotides after an exposure of 5 days.
Leukocytapheresis for patients with acute myeloid leukemia presenting with hyperleukocytosis and leukostasis: a contemporary appraisal of outcomes and benefits
Published in Expert Review of Hematology, 2020
Rory M. Shallis, Maximilian Stahl, Jan Philipp Bewersdorf, Jeanne E. Hendrickson, Amer M. Zeidan
The mechanism of leukemic cell dissemination from the bone marrow is poorly understood but is possibly related to varying expression of myeloblast cell adhesion receptors and a resultant decreased affinity for the bone marrow stromal microenvironment and increased selectin and integrin-mediated affinity for endothelial tissues [10–15]. Approximately 6–20% of AML patients present with hyperleukocytosis which is associated with a higher risk of three main complications: disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis [3,13,16–18]. DIC is a consequence of dysregulated coagulation pathways and is characterized by both an increased risk of microthrombi, venous and arterial thrombosis as well as bleeding [19,20]. Conflicting data report both a higher and lower relative risk of thrombosis in comparison to bleeding complications of DIC in AML patients at presentation [19,20]. DIC risk increases with WBC at presentation and about 10–30% of patients presenting with hyperleukocytosis will have DIC [3,13,16,17,19]. Platelet transfusion and both fibrinogen and factor replacement are mainstays of DIC-specific therapy which if not undertaken may hasten thrombosis and bleeding-related complications and even death [19]. Similarly, approximately 10% (though some studies report up to half) of AML patients at presentation are found to have TLS which is a result of hypermetabolic leukemic cell breakdown [21–24].
Cui bono? Finding the value of allogeneic stem cell transplantation for lower-risk myelodysplastic syndromes
Published in Expert Review of Hematology, 2020
Rory M. Shallis, Nikolai A. Podoltsev, Lohith Gowda, Amer M. Zeidan, Steven D. Gore
Normal hematopoiesis, an intricate interface of intermittent hematopoietic stem cell quiescence and strong cell cycle regulation, is subject to a variety of biological injuries increasing the risk of developing myelodysplastic syndrome (MDS) [1]. Perturbation of otherwise carefully controlled cellular pathways integral to signal transduction, ribonucleic acid (RNA) splicing and deoxyribonucleic acid (DNA) transcription can commit the myeloid compartment to dysplastic differentiation and aberrant proliferation [1]. The heterogeneity in function of these pathways when damaged predicts heterogeneity in the clinicopathologic phenotypes of MDS. As such, MDS is a varied collection of clonal, myeloid malignancies that manifest with (sometimes profound) peripheral cytopenias and a wide-ranging risk of disease progression, including acute myeloid leukemia (AML), and death [1,2]. These risks are characterized by a number of factors. Patient age, the degree/extent of cytopenias and myeloblast percentage at diagnosis, and cytogenetic abnormalities predict MDS-related risks over time. These metrics currently constitute the most commonly used standardized prognostic tools that estimate relevant risks associated with a diagnosis of MDS.
Precision medicine in acute myeloid leukemia: where are we now and what does the future hold?
Published in Expert Review of Hematology, 2020
Juan Eduardo Megías-Vericat, David Martínez-Cuadrón, Antonio Solana-Altabella, Pau Montesinos
Functional tests using predictive biomarkers of response are being tested, as for cyclin-dependent kinase (CDK)9 inhibitors. Alvocidib downregulates the transcription of myeloid cell leukemia-1 (MCL-1) gene, an antiapoptotic protein responsible in promoting cell survival of blast. Sensitivity to alvocidib is being investigated with BCL-2 homology domain 3 (BH3) profiling. This biomarker is based on mitochondrial depolarization following exposure to the peptide NOXA-BH3 when interacts with MCL-1, suggesting that the AML samples that are most responsive to alvocidib plus cytarabine and mitoxantrone (FLAM) are highly dependent on MCL-1 for survival [52]. Ongoing clinical trials included as eligibility criteria ≥40% myeloblast MCL-1 dependency determined by BH3 profiling in phase II trial in R/R AML (NCT02520011) [53] and in a phase I in untreated AML (NCT03298984).
Related Knowledge Centers
- Cell Growth
- Cell Potency
- Cytoplasm
- Granulocyte
- Bone Marrow
- Cell Nucleus
- Chromatin
- Nucleolus
- Cytokine
- Granulocyte Colony-Stimulating Factor