Showing papers on "Haematopoiesis published in 1985"

Expression of a foreign gene in myeloid and lymphoid cells derived from multipotent haematopoietic precursors

Abstract: Bone marrow cells infected with retroviral vectors carrying the bacterial neomycin resistance (neo) gene as a marker were used for long-term reconstitution of the haematopoietic system of irradiated mice. The neo gene is expressed in the myeloid and lymphoid lineages of these animals and an analysis of the sites of viral integration indicates that these lineages are derived from the same primitive multipotent cells.

Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo.

Abstract: We have investigated interferon as a mediator of hematopoietic suppression in bone marrow failure. Interferon production by stimulated peripheral blood mononuclear cells from patients with aplastic anemia was significantly higher than that observed in controls; spontaneous interferon production by these cells was also high for more than half of aplastic anemia patients. Circulating interferon, not detectable in normal individuals, was detected in 10 of 24 patients. Interferon is a potent inhibitor of hematopoietic cell proliferation and, therefore, may be the mediator of suppression in many in vitro models employing patients' cells and sera. The possible pathogenic importance of interferon in aplastic anemia was suggested by an increase in hematopoietic colony formation in vitro after exposure of bone marrow cells to antiinterferon antisera (277 +/- 71% increase for patients compared to 1.6 +/- 1.6% for normal individuals). Interferon levels in the bone marrow sera of aplastic anemia patients were high (mean = 203 international units (IU)/ml, n = 8), even in comparison to circulating levels in the same patients. Normal bone marrow sera also contained measurable interferon but at lower levels (41 IU/ml, n = 16), indicating that interferon may be a normal bone marrow product. High concentration of bone marrow interferon, possibly due to abnormal immunologic activity or a reaction to virus infection of the bone marrow, may mediate hematopoietic suppression in aplastic anemia patients.

Gene Expression in Mice after High Efficiency Retroviral-Mediated Gene Transfer

Abstract: A retroviral expression vector (N2) containing the selectable gene, neoR, has been used to determine the optimal conditions for infecting murine hematopoietic progenitor cells at high efficiency. After infected bone marrow cells were introduced into lethally irradiated mice, the presence, stability, and expression of the vector DNA sequences were analyzed either in individual spleen foci 10 days later or in the blood, bone marrow, and spleens of mice 4 months later. When bone marrow cells were cultured in medium containing virus with titers of more than 10(6) colony-forming units per milliliter in the presence of purified murine interleukin-3, more than 85 percent of the resulting foci contained vector DNA. This proviral vector DNA was intact. Efficient expression of the neoR gene was demonstrated in most of the DNA-positive foci examined. The spleens of reconstituted animals (over a long term) contained intact "vector DNA" and the blood and bone marrow expressed the neoR gene in some animals. Thus, a retroviral vector can be used to introduce intact exogenous DNA sequences into hematopoietic stem cells with high efficiency and with substantial expression.

Induction of c-fos during myelomonocytic differentiation and macrophage proliferation.

Abstract: Previous studies have suggested a role for c-fos in cellular differentiation in fetal membranes1–3, haematopoietic cells4,5 and teratocarcinoma stem cells6. In other cell types, such as fibroblasts, c-fos expression is normally very low, but is rapidly induced by peptide growth factors, implicating c-fos in growth control mechanisms7–10. Here, we show that the TPA (12-O-tetradecanoylphorbol-13-acetate)-induced macrophage-like differentiation of HL60 human promyelocytic precursor cells11,12 is accompanied by the induction of both c-fos mRNA and protein within 15 min after treatment, suggesting a functional role for c-fos in this differentiation system. In quiescent terminally differentiated macrophages, expression of c-fos is inducible by the macrophage-specific growth factor colony-stimulating factor-1 (CSF-1)13. The kinetics of c-fos induction, however, are entirely different from those in growth factor-stimulated fibroblasts, supporting the view that the c-fos gene product may serve different functions in different cell types.

Constitutive synthesis of interleukin-3 by leukaemia cell line WEHI-3B is due to retroviral insertion near the gene.

Abstract: Interleukin-3 (multi-CSF) is a multilineage haematopoietic growth regulator that initiates the proliferation and differentiation of multipotential stem cells. Complementary DNA clones encoding interleukin-3 (IL-3) have recently been isolated and the structure of the IL-3 gene determined. IL-3 is produced by T lymphocytes or T lymphomas only after stimulation with antigens, mitogens or chemical activators such as phorbol esters. The myelomonocytic leukaemia line WEHI-3B also produces IL-3 but its production is constitutive and the WEHI-3B cells do not appear to produce significant levels of any of the other lymphokines normally secreted by T lymphocytes after stimulation. It has been proposed that the genetic change leading to the constitutive expression of IL-3 may have been a key event in the development of this leukaemia. We report here that the constitutive synthesis of IL-3 by the WEHI-3B cell line is due to the insertion of an endogenous retrovirus-like element close to the 5' end of the gene. The insertion, an intracisternal A particle (IAP) genome, is positioned with its 5' long terminal repeat (LTR) close to the promoter region of the IL-3 gene, resulting in constitutive synthesis of IL-3.

Monoclonal antibodies to osteoclastomas (giant cell bone tumors): definition of osteoclast-specific cellular antigens.

Abstract: The cellular origin of the osteoclast, the major agent of bone resorption, remains controversial despite the demonstration that osteoclasts form by fusion of mononuclear cells that are ultimately derived from a bone marrow stem cell. One view is that they are the terminally differentiated progeny of mononuclear phagocytic cells. However, we have previously provided evidence, from functional and phenotypic studies of rodent and human osteoclasts, that raises the possibility that osteoclasts form a separate cell lineage from conventional hemopoietic cells and macrophages in particular. In an attempt to elucidate this question, we have used monoclonal antibody techniques to examine the relationship between osteoclasts and other bone marrow-derived cells. By using osteoclasts from osteoclastomas (giant cell tumors of bone) for immunizations, we have produced 11 mouse hybridomas secreting monoclonal antibodies reacting with osteoclasts in normal human fetal bone and a variety of neoplastic and non-neoplastic bone lesions. Eight antibodies in 4 reactivity sets have been shown to recognize membrane antigens, whereas a further 3 react with cytoplasmic determinants. In 7 there is no cross-reactivity with macrophages in a wide range of tissues, thus effectively differentiating between these two cell types. These antibodies will prove useful for the identification of osteoclasts in tissues and in the separation of their circulating precursors, thus allowing an experimental approach to be made to many of the outstanding questions regarding the developmental pathobiology of the osteoclast.

Molecular characterization and expression of the gene encoding human erythroid-potentiating activity.

Abstract: Erythropoietin is the primary physiological regulator of erythropoiesis; however, in vitro studies have identified another class of mediators which appear to be important in stimulating erythroid progenitors. These factors have generally been referred to as burst-promoting activities (BPA), because they stimulate the growth of early erythroid progenitors referred to as burst-forming units-erythroid (BFU-E) which give rise to colonies of up to thousands of haemoglobinized cells. We recently reported purification of a burst-promoting activity from medium conditioned by the Mo T-lymphoblast cell line infected with human T-cell lymphotropic virus type II (HTLV-II). This purified glycoprotein of relative molecular mass (Mr) 28,000 also stimulates colony formation by more mature erythroid precursors (CFU-E) and is therefore referred to as erythroid-potentiating activity (EPA). Purified EPA specifically stimulates human and murine cells of the erythroid lineage, unlike murine interleukin-3 (IL-3) which stimulates precursor cells from all haematopoietic lineages. We report here the isolation of a complementary DNA molecular clone encoding EPA and its use in producing EPA in COS (monkey) cells and CHO (Chinese hamster ovary) cells. We also define the organization of the EPA gene in human DNA.

Expression of the c-fms proto-oncogene during human monocytic differentiation.

Abstract: The McDonough strain of the feline sarcoma virus contains a transforming gene (v-fms) which contains partial nucleotide homology with proto-oncogenes encoding tyrosine kinases One of the v-fms-encoded products, gp140fms, is a cell surface transmembrane glycoprotein that may function as a growth factor receptor Although c-fms transcripts have been detected in placental trophoblasts and normal human bone marrow, the role of the c-fms gene product is unknown We now report that induction of monocytic, but not granulocytic, differentiation of human HL-60 leukaemic cells is associated with expression of c-fms, preceded by that of c-myc and c-fos Because c-fms transcripts are also detectable in peripheral blood monocytes and in blasts from certain patients with myelomonocytic leukaemia, the c-fms gene product may play a role in monocytic differentiation

1,25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells.

Abstract: The active metabolite of vitamin D known as 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is a major physiologic regulator of mineral metabolism in man. The compound is also a potent inducer of differentiation of a human promyelocytic leukemia cell line known as HL-60. The induction of differentiation of myeloid leukemia cells to functional end cells offers an appealing therapeutic prospect. We investigated the ability of 1,25(OH)2D3 both to induce in vitro the differentiation of blast cells taken from patients with acute myelogenous leukemia and to improve hematopoiesis in vivo in patients with the myelodysplastic syndromes (preleukemia). We found that high concentrations (10-6 M) of 1,25(OH)2D3 significantly induced the in vitro differentiation of blast cells as measured by morphology, phagocytosis, and superoxide production. A concentration of 10-9 M 1,25(OH)2D3 had no effect on blast cell differentiation. We gave 2 microgram/day of 1,25(OH)2D3 to 18 patients with myelodysplastic syndrome (preleukemia) in an attempt to improve their hematopoiesis. During therapy, their peak peripheral blood granulocyte, platelet, and macrophage concentrations were slightly elevated as compared to their baseline, starting levels. Eight patients had a partial or minor peripheral blood response to the compound during the administration of 1,25(OH)2D3. However, no patient showed significant improvement of peripheral blood cell or marrow blast cell counts by the end of the study (greater than or equal to 12 weeks) as compared to their starting levels. Seven of the patients developed leukemia before or by 12 weeks of treatment. Nine of the 18 patients developed hypercalcemia. Taken together, the study shows that high concentrations (10-6M) of 1,25(OH)2D3 can induce differentiation of leukemia blast cells in vitro, but the administration of 1,25(OH)2D3 to patients with the myelodysplastic syndromes (preleukemia) does not have an enduring therapeutic effect. Hypercalcemia prevented administering greater amounts of 1,25(OH)2D3. In the future, the use of new vitamin D analogs that induce hematopoietic cell differentiation without inducing hypercalcemia might allow the achievement of higher blood levels of the inducing compound and might be medically useful for selected preleukemic and leukemic patients.

Studies of interferon as a regulator of hematopoietic cell proliferation.

Abstract: The presence of interferon (IFN) in normal bone marrow and its abnormal production in aplastic anemia suggest that IFN may have normal regulatory roles and implicates them in the pathophysiology of bone marrow failure. We studied the effects of recombinant IFN (r-IFN) on hematopoietic colony formation in methylcellulose cultures of human bone marrow. Both recombinant IFN-gamma (r-IFN-gamma) and recombinant IFN-alpha (r-IFN-alpha) were potent suppressors of myeloid (CFU-C-derived) colony formation, with 50% inhibition occurring at 291 u/ml for r-IFN-gamma and 275 U/ml for r-IFN-alpha. Small amounts of r-IFN-gamma acted synergistically with r-IFN-alpha; as little as 5 U/ml of r-IFN-gamma increased inhibition of CFU-C-derived colony formation by r-IFN-alpha over threefold. Conversely, small amounts of r-IFN-alpha did not affect inhibition by r-IFN-gamma. Inhibition by r-IFN was highly dependent on culture conditions: reduction of the fetal calf serum concentration from 30% to 20%, a change that did not alter the plating efficiency of control cultures, significantly enhanced the action of r-IFN-gamma. Competition between positive hematopoietic factors and r-IFN was further demonstrated as increasing amounts of human placenta-conditioned media, used as a source of colony-stimulating activity, also partially blocked r-IFN inhibition. To determine if r-IFN could directly inhibit the proliferation of a progenitor cell, cells isolated from immature BFU-E-derived colonies, a population enriched for late erythroid progenitors and free of auxiliary cells, were tested; similar inhibition by r-IFN-gamma was observed with these isolated erythroid progenitors as with total bone marrow CFU-E. Although small amounts of r-IFN-gamma also increased inhibition of bone marrow CFU-E-derived colony formation by r-IFN-alpha, no synergy was demonstrable with isolated erythroid progenitor cells. Therefore, even though r-IFN can directly inhibit proliferation of a progenitor cell, auxiliary cells may be required for synergy between r-IFN-gamma and r-IFN-alpha.

Binding of 125I‐labeled granulocyte colony‐stimulating factor to normal murine hemopoietic cells

Abstract: The binding of granulocyte colony-stimulating factor (G-CSF) to murine bone marrow cells was investigated using a radioiodinated derivative of high specific radioactivity which retained full biological activity. The binding was time- and temperature-dependent, saturable and highly specific. The apparent dissociation constant for the reaction was 60-80 pM at 37 degrees C and 90-110 pM at 4 degrees C, similar to that found for the binding of G-CSF to murine leukemic cells (WEHI-3B D+) and significantly higher than the concentration of G-CSF required to stimulate colony formation in vitro. Autoradiographic analysis confirmed the specificity of binding since granulocytic cells were labeled but lymphocytes, erythroid cells and eosinophils were not. Blast cells and monocytic cells were partially labeled, the latter at low levels. In the neutrophilic granulocyte series, grain counts increased with cell maturity, polymorphs being the most heavily labeled but all cells showed considerable heterogeneity in the degree of labeling. Combination of Scatchard analysis of binding with autoradiographic data indicated that mature granulocytes from murine bone marrow exhibited 50-500 G-CSF receptors per cell.

The macrophage colony-stimulating factor, CSF-1.

Abstract: Publisher Summary This chapter discusses the macrophage colony-stimulating factor—that is, CSF The production of granulocytes and macrophages from immature hemopoietic progenitor cells in tissue culture is dependent on the presence of a group of specific growth factors These factors are termed the CSFs because in semisolid culture media they stimulate individual hemopoietic progenitor cells to form colonies of granulocytes and macrophages They are believed to regulate granulocyte and macrophage production in intact animals although their in vivo effects have not been elucidated At least 4 CSF subclasses can be defined by the kind of mature cells they produce in culture The CSF bioassay is based on the CSF-dependent formation of colonies of granulocytes and/or macrophages by bone marrow cells cultured in semisolid agar or methyl cellulose medium For large numbers of assays the agar culture method is more rapid and less expensive However, good cellular morphology of stained colony cells is more easily obtained with colonies from methyl cellulose cultures Bioassays may be carried out in a number of species including chickens or man Methods for the bioassay of murine and human CSFs are also described further in the chapter

Biological activities of a human pluripotent hemopoietic colony stimulating factor on normal and leukemic cells.

Abstract: We studied the biological effects of pluripoietin, a human pluripotent hemopoietic colony-stimulating factor (CSF) purified from the 5637 bladder carcinoma cell line. We found that this human CSF appears to be a unique hemopoietic growth factor, differing from interleukin 3 (IL-3) by virtue of its leukemia differentiating activity in mouse and man, and from mouse granulocyte CSF, which does have differentiation-inducing activity, but lacks pluripoietic activity. In addition, differences from IL-3 were observed in cross-species activity on normal and leukemic cells.

Synergism between hemopoietic growth factors (HGFs) detected by their effects on cells bearing receptors for a lineage specific HGF: Assay of hemopoietin‐1

Abstract: The preceding paper describes a new approach to the detection and assay of growth factors for developmentally early multipotent hemopoietic cells (Bartelmez et al., J. Cell. Physiol., 1985). This approach, involving measurement of the increase in the number of receptors for the mononuclear phagocyte specific hemopoietic growth factor (HGF), colony stimulating factor-1 (CSF-1), in cultures of developmentally early murine cells incubated with putative HGFs, has been used to define and assay hemopoietin-1. Hemopoietin-1 (Mr approximately 20,000) is found in the medium derived from serum-free cultures of cells of the human urinary bladder carcinoma line 5637. In contrast to both hemopoietin-2 and CSF-1, which also stimulate an increase in CSF-1 receptor numbers in cultures of developmentally early hemopoietic cells, hemopoietin-1 alone has no detectable effect. However, hemopoietin-1 exhibits dramatic synergism with CSF-1. In the presence of CSF-1, hemopoietin-1 stimulates the proliferation of developmentally earlier cells than those that respond to either CSF-1 alone or hemopoietin-2 alone or their combination. These cells proliferate for at least 3 days with no alteration of the average CSF-1 receptor density. However, by 5 days of incubation, the progeny of developmentally early hemopoietic cells that have proliferated in response to hemopoietin-1 + CSF-1 exhibit an approximately tenfold increase in the average CSF-1 receptor density per cell, which immediately precedes their differentiation to adherent mononuclear phagocytes. As hemopoietin-1 does not possess colony stimulating or burst promoting activities for murine bone marrow cells, but acts on multipotent hemopoietic cells, the analysis of the mechanism of its synergistic effects with HGFs such as CSF-1 are of special relevance to the regulation of early events in hemopoiesis.

Developmental regulation of c-myb in normal myeloid progenitor cells

Abstract: Hematopoietic tissues and some leukemic cell lines express elevated levels of c-myb transcripts. We have separated a subpopulation of chicken embryo yolk sac cells that represents about 5% of the yolk sac hematopoietic cells and appears to contain all of the detectable c-myb transcripts. The level of myb expression in this cell population is higher than previously reported for any normal cell population and is in the range of that found in cells transformed by avian myeloblastosis virus and E26 virus. Since the myb gene probe used also detects full-length viral transcripts as well as the v-myb mRNA, it appears that the level of expression of c-myb in this normal population may exceed that found in some transformed cell populations that depend on v-myb to maintain the transformed phenotype. This c-myb-expressing cell population has been identified as primarily M-CFC, the committed progenitor for the macrophage lineage. As cells differentiate to the promonocyte stage there is an abrupt decrease in c-myb expression of greater than 100 fold. These studies thus describe a normal cell population that expresses c-myb at levels similar to the level of v-myb in cells that depend on v-myb for the maintenance of their transformed phenotype. Furthermore, these studies provide direct evidence for the developmental regulation of c-myb during the process of normal macrophage differentiation.

Specific binding of radioiodinated granulocyte-macrophage colony-stimulating factor to hemopoietic cells.

Abstract: The hemopoietic growth factor granulocyte-macrophage colony-stimulating factor, GM-CSF, specifically controls the production of granulocytes and macrophages. This report describes the binding of biologically-active 125I-labeled murine GM-CSF to a range of hemopoietic cells. Specific binding was restricted to murine cells and neither rat nor human bone marrow cells appeared to have surface receptors for 125I-labeled GM-CSF. 125I-Labeled GM-CSF only appeared to bind specifically to cells in the myelomonocytic lineage. The binding of 125I-labeled GM-CSF to both bone marrow cells and WEHI-3B(D+) was rapid (50% maximum binding was attained within 5 min at both 20 degrees C and 37 degrees C). Unlabeled GM-CSF was the only polypeptide hormone which completely inhibited the binding of 125I-labeled GM-CSF to bone marrow cells, however, multi-CSF (also called IL-3) and G-CSF partially reduced the binding of 125I-labeled GM-CSF to bone marrow cells. Interestingly, the binding of 125I-labeled GM-CSF to a myelomonocytic cell line, WEHI-3B(D+), was inhibited by unlabeled GM-CSF but not by multi-CSF or G-CSF. Scatchard analysis of the binding of 125I-labeled GM-CSF to WEHI-3B(D+) cells, bone marrow cells and peritoneal neutrophils indicated that there were two classes of binding sites: one of high affinity (Kd1 = 20 pM) and one of low affinity (Kd2 = 0.8-1.2 nM). Multi-CSF only inhibited the binding of 125I-labeled GM-CSF to the high affinity receptor on bone marrow cells: this inhibition appeared to be a result of down regulation or modification of the GM-CSF receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Specific expression of the human cellular fps/fes-encoded protein NCP92 in normal and leukemic myeloid cells.

Abstract: We have found that both an antibody directed against a synthetic peptide representing an amino acid sequence of the conserved kinase domain of transforming protein P140 of Fujinami sarcoma virus and a regressing tumor antiserum recognized the products of the c-fps/fes genes of both avian and mammalian cells. The anti-peptide antibody also recognized a 94-kilodalton protein that was related to but distinct from the c-fps/fes product in structure and in tissue distribution. A 92-kilodalton protein, NCP92, was found to be the mammalian counterpart of the previously identified avian c-fps/fes protein NCP98 by its structural similarity to NCP98, its associated tyrosine kinase activity, and its similar tissue distribution. The highest levels of NCP92 were found in tissue macrophages and in bone marrow. In bone marrow NCP92 expression was restricted to cells of the monocyte/macrophage and granulocyte lineages. That the expression of NCP92 is limited to these cell types was confirmed by the analysis of murine and human hematopoietic tumors representing different cell lineages: NCP92 was positive in leukemic cells of granulocytic and monocytic origin but not in B-lymphocytic, T-lymphocytic, or erythroid tumor cells. The expression of NCP92 seems to be related to the capacity of myeloid cells to differentiate and to respond to certain colony-stimulating factors.

Expression of the mammalian c-fes protein in hematopoietic cells and identification of a distinct fes-related protein

Abstract: The avian c-fps and mammalian c-fes proto-oncogenes are cognate cellular sequences. Antiserum raised against the P140gag-fps transforming protein of Fujinami avian sarcoma virus specifically recognized a 92,000-Mr protein in human and mouse hematopoietic cells which was closely related in structure to Snyder-Theilen feline sarcoma virus P87gag-fes. This polypeptide was apparently the product of the human c-fes gene and was therefore designated p92c-fes. Human p92c-fes was associated with a tyrosine-specific protein kinase activity in vitro and was capable of both autophosphorylation and phosphorylation of enolase as an exogenous protein substrate. The synthesis of human and mouse p92c-fes was largely, though not entirely, confined to myeloid cells. p92c-fes was expressed to relatively high levels in a multipotential murine myeloid cell line, in more mature human and mouse granulocyte-macrophage progenitors, and in differentiated macrophage like cells as well as in the mononuclear fraction of normal and leukemic human peripheral blood. p92c-fes was not found in erythroid cells, with the exception of a human erythroleukemia line which retains the capacity to differentiate into macrophage like cells. These results suggest a normal role for the p92c-fes tyrosine kinase in hematopoiesis, particularly in granulocyte-macrophage differentiation. In addition, a distinct 94,000-Mr polypeptide, antigenically related to p92c-fes, was identified in a number of hematopoietic and nonhematopoietic human and mouse cells and was also found to be associated with a tyrosine-specific protein kinase activity.

Generation of functional clonal cell lines from human bone marrow stroma

Abstract: Five clonal human bone marrow stromal cell lines were isolated from the adherent cell populations in long-term liquid cultures after transfection with the recombinant plasmid pSV3gpt. All the cell-line feeder layers and their conditioned media stimulated the proliferation of committed granulomonocytic stem cells (CFUc) from human bone marrow. The size and number of early erythroid stem cell (BFUe)-derived colonies were significantly increased when in the presence of 10% conditioned medium from the cell lines. Furthermore, a substantial number of mixed colonies with erythroid components were observed in the cultures in the presence of erythropoietin and conditioned medium. These findings suggest that the human bone marrow stromal cell lines obtained after transfection with pSV3gpt may be extremely useful in identifying the hematopoietic factors derived from the hematopoietic microenvironment and in analyzing their mechanism of action.

Changes in hemopoietic tissue of rainbow trout under influence of stress

Abstract: As in higher vertebrates, stress increases the susceptibility of fishes to disease. This effect is accompanied by changes in circulating white blood cells: the number of lymphocytes decreases while the number of granulocytes increases. Investigations were therefore undertaken to determine in what ways stress induces changes in hemopoietic organs, particularly spleen and head kidneys of rainbow trout Salmo gairdneri Handling and social conflict were used as stressors. These psychic stimuli are typically encountered in aquaculture and under laboratory conditions. Under the influence of both stressors hemopoiesis in spleen and head kidney is disturbed. Blast cells become rare or disappear completely from the tissue. The numbers of mature, intact PMN cells and of small lyrnphocytes also decrease. Hypertrophic macrophage-like cells with vacuolized cytoplasm appear in increasing numbers. They develop mainly from immature PMN and reticuloendothelial cells. They swell continuously while undergoing evident disintegration. At the same time, destruction of erythrocytes proceeds at an increased rate. The high numbers of macrophage-like cells may indicate that the stresson initially stimulate the defense mechanisms and thereby serve an adaptive function. Possibly, under continued stress, their proteolytic enzymes begin to damage the body's own blood cells. The decreased production of new blood cells and the increased destruction of immune-competent cells still present seem finally to contribute to disease susceptibility under stress.

Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications.

Abstract: The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities.