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PubMed2000

Late Myelosuppressive Action of Programmed Chemotherapy in Acute Lymphoblastic Leukemia in Children.

The capability of peripheral blood leukocytes and bone marrow cells to spontaneous apoptosis was studied in 36 children with ALL remission at various periods after polychemotherapy withdrawal. The enhancement of apoptotic activity has been revealed to be the universal mechanism of delayed effect of antileukemic chemotherapy for all the compartments of hemopoiesis, including granulocyte/macrophage precursors. The expression of this phenomenon is decreasing with the time period elapsed after treatment withdrawal. However, approximation analysis shows that the recovery of normal values of blood cell apoptosis occurs not earlier than 8 years after therapy withdrawal. Therein, in should be noted that the numbers of leukocytes don't differ from normal values at all the periods of observation. The growth of proliferative potential for precursor cells and the increased proportion of proliferating granulocyte pool of bone marrow are shown to be the probable mechanisms contributing to compensation of enhanced ability of blood cells to apoptosis.

Journal Article↗
PubMed1989

Osteoclast-like cells formed in long-term human bone marrow cultures express a similar surface phenotype as authentic osteoclasts.

Long-term cultures of human bone marrow form multinucleated cells (MNC) with many functional characteristics of osteoclasts including: expression of tartrate-resistant acid phosphatase, appropriate responses to osteotropic hormones, calcitonin-induced contraction and formation of resorption lacunae on calcified matrices. However, it is unclear if these cells express similar surface antigens as expressed by authentic osteoclasts, since they form on plastic surfaces in the absence of bone. Bone may be required to complete the differentiation process for osteoclasts. Therefore, we have examined the surface phenotype of MNC and compared it with that of osteoclasts freshly isolated from bone, to determine if MNC express similar surface antigens, and if MNC express antigens which identify their cellular origin. Similar to bone-derived osteoclasts, MNC formed in long-term human bone marrow culture expressed osteoclast-specific antigens (detected by monoclonal antibodies 13c2 and 23c6) and did not express Fc receptors, T cell specific antigens, most myeloid antigens or mature macrophage antigens. In contrast to authentic osteoclasts, MNC reacted with a monoclonal antibody (Mol) which identifies an antigen present on myeloblasts, monocytes, granulocytes, and null cells from human peripheral blood and bone marrow. MNC also reacted with the monoclonal antibody My11, which is present on CFU-GM, the granulocyte-macrophage colony-forming cell, the probable precursor for MNC. These data demonstrate that MNC formed in long-term human marrow cultures express a similar surface phenotype to osteoclasts. This phenotype is different from that expressed by macrophage polykaryons. In addition, MNC also expressed monocyte-related antigens (My11, Mol), suggesting that are derived from or related to the monocytic lineage.

Animals↗
PubMed1987

Immunohistochemical characterization of a 183 KD myeloid-specific-DNA-binding protein in B5 fixed, paraffin-embedded tissues, and bone marrow aspirates by monoclonal antibody BM-1.

A monoclonal antibody, designated BM-1, which is reactive in B5 formalin-fixed, paraffin-embedded tissues, has been generated against a cytoplasmic and nuclear antigen expressed in human myeloid precursor cells and derived leukemias. Using the avidin-biotin-complex immunoperoxidase procedure, BM-1 was found to stain selectively myeloid precursor cells in normal bone marrow and mature granulocytes in the blood. In a screen of 26 normal adult and fetal human organs fixed in B5 formalin, BM-1 was negative in all nonhematopoietic tissues with the exception of tissue granulocytes and scattered cells in the peripheral cortex of the thymus. Likewise a screen of 30 solid tumor cell lines including a spectrum of carcinomas, sarcomas, and neural-derived tumors was negative. BM-1 was also negative with 21 T and B cell lymphomas and 11 Hodgkin's disease tumors. A preliminary study of tumors of the hematopoietic system revealed that BM-1 was reactive with M2 and M3 acute myelogenous leukemias (AML), chronic myelogenous leukemias (CML) and myelomonocytic leukemias, and granulocytic sarcomas. M1, M4, M5, and M6 AML clot preparations were negative in this study, indicating that BM-1 may have a role in the histopathologic diagnosis of myelogenous leukemia. Myeloid leukemic cell lines HL-60, ML-2, KG1, and TPH-1-O showed BM-1 nuclear and/or cytoplasmic reactivity in a subpopulation of cells, but erythroid and lymphoid leukemias and all lymphoma cell lines were negative. Immunoperoxidase studies of a panel of fetal tissues showed BM-1 positive cells in the peripheral cortex of the thymus and portal myelopoietic regions of the liver at 18 weeks gestation. Finally, DNA-cellulose and solid phase radioimmunoassay (RIA) techniques developed in our laboratory demonstrate that the BM-1 antigenic domain is reactive only after binding to eukaryotic but not prokaryotic single- or double-stranded DNA. Immunoblot techniques using a DNA-cellulose purified protein sample revealed that BM-1 recognizes a 183 kD protein. These studies indicate that BM-1 is recognizing a myeloid-specific antigen that, because of its DNA binding characteristics, may have an important role in the differentiation of myeloid cells at the molecular level.

Animals↗
PubMed1980

Lactoferrin deficiency as a consequence of a lack of specific granules in neutrophils from a patient with recurrent infections. Detection by immunoperoxidase staining for lactoferrin and cytochemical electron microscopy.

Neutrophils from a boy suffering from recurrent infections were found to be totally deficient in specific granules when studied by electron microscopy. In contrast, myeloperoxidase-containing azurophil granules were increased in number. This deficiency of specific granules could be detected at the light-microscopic level using an immunocytochemical technique to demonstrate the absence of lactoferrin. Neutrophils also exhibited abnormal nuclear segmentation, nuclear clefts, an abnormally weak cytochemical reaction for alkaline phosphatase, and an increased number of mitochondria and ribosomes. Some granulocytic precursors were abnormal, and many of these cells were phagocytosed by macrophages in the bone marrow. Despite these multiple abnormalities and the history of severe pyogenic infection, the in vitro bactericidal capacity of the neutrophils was within normal limits, and normal degranulation of azurophil granules occurred following phagocytosis. The precise mechanism by which the deficiency of specific granules in this patient led to an enhanced in vivo susceptibility to infection therefore remains obscure. However, attention is drawn to the fact that in three previously described cases of specific granule deficiency a history of recurrent infections was present.

Bacterial Infections↗
PubMed1986

Human pluripotent hemopoietic colony stimulating factor: activities on human and murine cells.

Human pluripotent colony stimulating factor (Pluripoietin) was shown to act synergistically with human pluripotent alpha-like colony-stimulating activity (Pluripoietin-alpha) supporting the proliferation and differentiation of human CFU-GM progenitor cells in vitro, increasing colony size and numbers. In addition, Pluripoietin enhanced cytotoxic activity of mature human neutrophil granulocytes in an antibody-dependent cellular cytotoxicity assay. Biological activities of Pluripoietin known so far suggest great potentials for clinical use. Preclinical in vivo studies of Pluripoietin in different disease situations may be feasible in mice, because Pluripoietin is active on granulocyte precursors and on a variety of other murine cells.

Animals↗
PubMed1994

Fluorescence in situ hybridization (FISH) detection of trisomy 8 in myeloid cells in chronic myeloid leukemia (CML): a study of archival blood and bone marrow smears.

Patients in accelerated phase or blast crisis of chronic myeloid leukemia (CML) frequently develop clonal cytogenetic abnormalities in addition to the Philadelphia chromosome. Using a DNA probe directed to the centromere of chromosome 8, we performed fluorescence in situ hybridization (FISH) on archival Wright-stained blood and bone marrow smears of seven patients with CML and with a known +8 clone by metaphase cytogenetics to determine the distribution of +8 in interphase cells. All slides had been stored at ambient temperature for 12-26 months. The bone marrow aspirate smears of 21 non-leukemic patients served as controls. Trisomy 8 was demonstrated in all myeloid cell lines including the neutrophils, basophils, eosinophils, monocytes, and erythroid precursors, but not in the lymphocytes. The extra chromosome 8 was present in mature segmented granulocytes as well as more immature precursors. The percentage of +8 cells was highest in specimens from patients with CML in myeloid blast crisis (mean 64%), followed by those in accelerated phase (mean 39%). Three specimens from patients in morphologic chronic phase showed the lowest percentage of +8 cells (mean 13%). One patient was studied twice and showed a substantial expansion of +8 cells with progression from accelerated phase to myeloid blast crisis. Compared to metaphase cytogenetics, the proportion of +8 cells detected by FISH was often lower. We conclude that the acquisition of trisomy 8 in CML occurs in a pluripotent myeloid stem cell apparently incapable of expressing mature lymphoid phenotype, and that morphologic progression of disease is generally associated with an expansion of the +8 component.

Adult↗
PubMed1998

CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors.

The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) regulates a number of myeloid cell-specific genes. To delineate the role of C/EBPalpha in human granulopoiesis, we studied its expression and function in human primary cells and bipotential (granulocytic/monocytic) myeloid cell lines. We show that the expression of C/EBPalpha initiates with the commitment of multipotential precursors to the myeloid lineage, is specifically upregulated during granulocytic differentiation, and is rapidly downregulated during the alternative monocytic pathway. Conditional expression of C/EBPalpha alone in stably transfected bipotential cells triggers neutrophilic differentiation, concomitant with upregulation of the granulocyte-specific granulocyte colony-stimulating factor receptor and secondary granule protein genes. Moreover, induced expression of C/EBPalpha in bipotential precursors blocks their monocytic differentiation program. These results indicate that C/EBPalpha serves as a myeloid differentiation switch acting on bipotential precursors and directing them to mature to granulocytes.

CCAAT-Enhancer-Binding Proteins↗
PubMed1985

Haemopoietic stem cell: a new concept.

It is generally accepted that morphologically recognizable bone marrow (BM) cells are derived from progenitor cells committed to a specific line of haematopoietic differentiation [51]. The origin and morphological identity of such progenitor cells is not yet known and the question, whether there is a single pluripotent haematopoietic stem cell (HSC) or a variety of stem cells each with a capacity of self-replication and maintenance is still unresolved [37]. Although progress has been made in segregating [43, 47, 49, 64] various progenitor cells from one another and functional assays [11, 17, 42] have significantly promoted the study of haemopoietic precursor cells, morphological investigations were less rewarding. Even after enrichment, the morphology of haemopoietic stem- and colony-forming cells only remained hypothetical, 'candidate stem cells' [3], because their precursor cell qualities could not be deduced from their morphology, but only retrospectively, and statistically from their function, i.e. in vitro colony-formation or in-vivo haemopoietic reconstitution from an enriched cell suspension [58]. We postulate from our studies on semi-thin sections of undecalcified BM from healthy human fetuses, normal adults and patients with acute myeloid leukaemia (AML) and chronic granulocytic leukaemia (CGL) that the endosteal cells are the precursors of all haematopoietic cells in the bone marrow and are also capable of transformation into either stromal (fibroblast-like cells) or bone-related cells (osteoblasts and osteoclasts).

Bone Marrow↗
PubMed1983

The properties of human fetal bone marrow stromal and hemopoietic cells.

The capacity of fetal bone marrow to form stromal cell colonies, granulocyte-macrophage colonies, stromal cell monolayers and to produce granulocyte-macrophage colony stimulating activity from these monolayers was evaluated in comparison to adult bone marrow. Granulocyte-macrophage colony formation on routine feeder layers was approximately equal in both cases. The fetal bone marrow colonies were larger in size than those from adult precursors. There were at least ten times more stromal cell precursors in fetal bone marrow than in adult bone marrow. The fetal bone marrow stromal cell monolayer formed within 7-12 days whereas adult stromal monolayer formation required 3-4 weeks. Fetal bone marrow stromal cell monolayer produced granulocyte-macrophage colony-stimulating activity (GM-CSA) effective only for fetal GM precursors, whereas adult bone marrow produces GM-CSA effective for fetal and adult normal and CML bone marrow.

Adult↗
PubMed1985

Opposing effects of dexamethasone on the clonal growth of granulocyte and macrophage progenitor cells and on the phagocytic capability of mononuclear phagocytes at different stages of differentiation.

Dexamethasone, a synthetic glucocorticosteroid, was shown to modulate the colony-stimulating factor-dependent clonal growth of myeloid progenitor cells in semisolid agar cultures, enhancing the formation of granulocyte colonies (50-100%) and suppressing the formation of macrophage colonies (75-97%). Modulation of the pattern of myeloid colony formation by dexamethasone (12-125 nM) was brought about when the steroid was administered to 6-day cultures at the time of culture initiation and up to 72 hr later. Dexamethasone inhibited myeloid cell proliferation when administered to 5-day liquid cultures at culture initiation and up to 96 hr later. Dexamethasone (12-250 nM) also enhanced the phagocytic activity of bone marrow-derived mononuclear phagocytes toward heat-killed (HK) yeast cells (up to 100%) and IgG-coated sheep red blood cells (up to 60%). Enhancement of the phagocytic capability depended critically on the stage in culture at which dexamethasone was administered. Exposure to dexamethasone for 28 hr up to 96 hr of 96-hr cultures of bone marrow cells did not lead to a modulation of phagocytic activity of the developing mononuclear phagocytes. The presence of dexamethasone during the critical period of 96 hr to 120 hr after culture initiation led to an enhanced phagocytic capability, which was statistically significant already 12 hr after the administration of the glucocorticoid. Dexamethasone induced an enhanced phagocytic activity when administered at any time after culture initiation provided that it was in culture during this critical period. When added at 120 hr of culture, dexamethasone no longer enhanced the phagocytic capability of mononuclear phagocytes and when added later than 156 hr of culture suppressed it. Dexamethasone also suppressed (up to 68%) the phagocytic capability of resident and elicited peritoneal macrophages. The results suggest that glucocorticoids shift the balance of granulocyte vs. macrophage formation at early stages of precursor cell differentiation. Reduction in mononuclear phagocyte growth and enhancement of its phagocytic capability might reflect accelerated differentiation/maturation steps. The inhibitory effect of dexamethasone on macrophage formation and on the phagocytic capability of mature mononuclear phagocytes and peritoneal macrophages might be a relevant aspect of the in vivo immune suppression encountered after glucocorticoid administration.

Animals↗
PubMed1990

Kinetic studies of pyruvate kinase during in vitro differentiation of GM-CFC haemopoietic precursor and bone marrow cells in mice.

Pyruvate kinase studies in the granulocyte-macrophage lineage during in vitro differentiation have been performed using culture techniques on GM-CFC cells and a study has also been done in bone marrow cells. The enzyme exhibits biphasic behaviour with respect to both of its substrates in cells derived from in vitro cultures at 5 and 7 days of incubation period. However in bone marrow cells these kinetics are only observed for ADP. The different kinetic behaviour of pyruvate kinase toward Fru-1,6-P2, Ala, Phe and ATP in the three cellular populations allows us to conclude that the expression of pyruvate kinase is associated with the differentiation of these cells.

Adenosine Diphosphate↗
PubMed2006

Neurogenin 3 and the enteroendocrine cell lineage in the adult mouse small intestinal epithelium.

It is thought that small intestinal epithelial stem cell progeny, via Notch signaling, yield a Hes1-expressing columnar lineage progenitor and an Atoh1 (also known as Math1)-expressing common progenitor for all granulocytic lineages including enteroendocrine cells, one of the body's largest populations of endocrine cells. Because Neurogenin 3 (Neurog3) null mice lack enteroendocrine cells, Neurog3-expressing progenitors derived from the common granulocytic progenitor are thought to produce the enteroendocrine lineage, although more recent work indicates that Neurog3+ progenitors also contribute to non-enteroendocrine lineages. We aimed to test this model and better characterize the progenitors leading from the stem cells to the enteroendocrine lineage. We investigated clones derived from enteroendocrine precursors and found no evidence of a common granulocytic progenitor that routinely yields all granulocytic lineages. Rather, enteroendocrine cells are derived from a short-lived bipotential progenitor whose offspring, probably via Notch signaling, yield a Neurog3+ cell committed to the enteroendocrine lineage and a progenitor committed to the columnar lineage. The Neurog3+ cell population is heterogeneous; only about 1/3 are slowly cycling progenitors, the rest are postmitotic cells in early stages of enteroendocrine differentiation. No evidence was found that Neurog3+ cells contribute to non-enteroendocrine lineages. Revised lineage models for the small intestinal epithelium are introduced.

Animals↗
PubMed1985

Separation by velocity sedimentation of human haemopoietic precursors forming colonies in vivo and in vitro cultures.

Cells which give rise to granulocyte-macrophage colonies under the influence of peripheral blood white cells (CFU-c (WBC] and Mo T cell conditioned medium (CFU-c (Mo] sedimented at a faster rate than the cells which form mixed erythroid-granulocytic colonies in methylcellulose in vitro (CFU-mix) and granulocytic (CFU-dg) and megakaryocytic (CFU-dm) colonies in diffusion chambers in mice. Despite identical peak sedimentation rate for the two CFU-c populations, sedimentation profiles suggest that they are heterogeneous with respect to size. A proportion of CFU-c (Mo) may be identical with CFU-dg and CFU-mix. Sedimentation profiles for cells which give rise to mixed colonies in vitro (CFU-mix) and to granulocytic colonies in diffusion chambers in cyclophosphamide pretreated mice (CFU-dg (CY] and in Mo conditioned medium treated mice (CFU-dg (Mo] were similar. On the average CFU-dm sedimented somewhat slower than CFU-dg. These and other observations suggesting a close relationship between CFU-dg and multipotential haemopoietic precursors are discussed.

Bone Marrow Cells↗
PubMed1977

Expression of Ia-like antigen molecules on human granulocytes during early phases of differentiation.

Human B lymphocyte antigens analogous to the murine Ia determinants were found on myeloblasts and promyelocytes but not on more mature granulocytes. This was apparent by fluorescent staining with both human alloantisera and rabbit antisera to the isolated Ia-like proteins. The cells of patients with chronic myelocytic leukemia showed this difference especially clearly. Separation of the myeloblasts and promyelocytes by multistep density gradient fractionation produced a marked enrichment of the positive cells. The remaining cells from higher density fractions were more-mature neutrophils that were essentially negative. In acute myeloid leukemia, in which myeloid cells early in differentiation predominate, the vast majority of cells were strongly positive. Similar results were obtained with normal bone marrow cells. Here also, only the early forms of the myeloid series separated by gradient centrifugation had Ia antigens. Evidence was also obtained for the presence of Ia determinants on cells with the appearance of early erythroid precursors. Support for the presence of the Ia determinants on granulocyte-macrophage committed stem cells was provided by the inhibition of granulocyte colony formation in agar cultures following preincubation of normal bone marrow with antiserum and complement. Cross absorptions with purified preparations of immature cells provided evidence for the close similarity of the antigenic determinants on both myeloblasts and B cells. A 28,000-37,000-dalton bimolecular complex obtained from myeloblast membranes contained the Ia determinants and was similar to that obtained from peripheral blood B cell membranes.

B-Lymphocytes↗
PubMedDate not supplied

Acute effects of prechemotherapy filgrastim administration on late hematopoietic progenitor cells.

Administration of filgrastim influences the proliferative kinetics of myeloid progenitor cells. Even after it is discontinued, increased levels of cycling of granulocyte precursors are sustained for approximately 4 days. Beginning chemotherapy during this period of enhanced marrow activity can cause great damage to late, and possibly early, progenitor cell pools. Peripheral blood samples were collected from two research study patients who were prospectively randomized to receive filgrastim by different schedules after chemotherapy. The mononuclear cell fraction was analyzed by clonogenic progenitor cell assay and flow cytometry. Ex vivo and clinical findings were correlated with filgrastim and chemotherapy administration times. Although quantitative recovery of circulating neutrophils occurred, a substantial decrease in peripheral blood progenitor cells was observed when chemotherapy was started 72 hours after cessation of filgrastim therapy. Neutrophil recovery alone is not a precise index of short-term marrow granulocyte progenitor status. Starting chemotherapy within 72 hours of filgrastim therapy is biologically, and possibly, clinically relevant.

Adult↗
PubMed1969

Serine requirement in leukemic and normal blood cells.

In a serine-deficient medium, cells from humangt chronic granulocytic leukemia and normal human bone marrow exhibited a marked inhibition of incorporation of-radioactive precursors of DNA, RNA, and protein into an acid insoluble cell fraction. Normal diploid human fibroblasts did not exhibit inhibition without serine. Chronic granulocytic leukemia and normal marrow cells were essentially unable to synthesize C(14)-serine from C(14)-glucose, while human diploid fibroblasts were highly capable of this synthesis.

Alanine↗
PubMed2003

Transient expression of PU.1 commits multipotent progenitors to a myeloid fate whereas continued expression favors macrophage over granulocyte differentiation.

OBJECTIVES: The Ets-family transcription factor PU.1 is expressed specifically in the hematopoietic system, in which it is absolutely required for the generation of B lymphocytes and macrophages. In contrast, overexpression of PU.1 blocks terminal differentiation of the erythroid lineage, in which it can act as an oncogene. In this study we used a multipotential progenitor cell line to examine the effects of PU.1 overexpression on myeloerythroid commitment within a single model system. MATERIALS AND METHODS: PU.1 cDNA was introduced transiently and stably into the multipotent, nonleukemic hemopoietic cell line FDCPmix. Transiently transfected cells were isolated by fluorescence-activated cell sorting within 18 hours of transfection. Stable transfectants were selected by antibiotic resistance over a number of weeks. The effects of short- and long-term overexpression of PU.1 on self-renewal, proliferation, and differentiation were investigated. RESULTS: A transient pulse of expression in multipotent progenitor cells eliminated the options of self-renewal and erythroid differentiation, resulting in commitment to the myeloid lineage. However, this transient pulse of expression did not affect the subsequent lineage choice of bipotent granulocyte/macrophage progenitors. In contrast, continuous expression of PU.1 resulted in a strong bias toward macrophage rather than granulocyte differentiation. CONCLUSIONS: These results demonstrate promyeloid effects of PU.1 at two distinct stages of hematopoiesis.

Animals↗