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PubMed2005

Aldehyde dehydrogenase activity as a marker for the quality of hematopoietic stem cell transplants.

Taking advantage of fluorescent substrates for their metabolic marker aldehyde dehydrogenase (ALDH), hematopoietic stem cells (HSC) were defined as SSC(lo)ALDH(br) - reflecting their low orthogonal light scattering and bright fluorescence intensity in flow cytometry. Based thereon, we investigated the usefulness of ALDH activity for characterizing HSC graft quality, particularly under stress conditions. We first compared the expression of ALDH vs CD34 in bone marrow and peripheral blood stem cell (PBSC) samples over 7 days. We noted that (i) only ALDH activity but not CD34 expression strongly reflected colony-forming ability over time, and that (ii) PBSC grafts stored at room temperature lost most of their progenitor cells within just 48 h. We then retrospectively related ALDH and CD34 expression as well as granulocyte-macrophage colony-forming units (CFU-GM) potential for 19 cryopreserved allogeneic PBSC grafts to engraftment data. Strikingly, in all six patients who received markedly decreased numbers of SSC(lo)ALDH(br) cells, this was associated not only with almost complete loss of CFU-GM potential but also with delayed establishment/permanent absence of full hematopoietic donor cell chimerism, whereas all other patients showed early complete donor chimerism. In conclusion, we suggest to measure ALDH activity as a surrogate marker for HSC activity, and to transport and store PBSC under controlled cooling conditions.

Aldehyde Dehydrogenase↗

PubMed1996

A hematopoietic organ-specific 49-kD nuclear antigen: predominance in immature normal and tumor granulocytes and detection in hematopoietic precursor cells.

A 49-kD protein was specifically detected in hematopoietic organs by Western blotting with a novel mouse monoclonal antibody (B92) raised against stromal cells. The protein was found in the immunizing cells using a sensitive method. However, its detection in the bone marrow by the B92 antibody seemed to stem from the abundance of p49 in immature cells of the myeloid lineage. Study of the bone marrow following in vivo irradiation or 5-fluorouracil (5-FU) treatment, in vitro culture with differentiation-inducing factors and long-term culture, and cell sorting all pointed in the same direction: the protein was found in early myeloid cells and in hematopoietic precursor cells. These results were in accordance with the specific presence of p49 in primary radiation-induced myeloid leukemia and its absence in spontaneous B lymphoma. Immunofluorescent staining using B92 antibody detected a nuclear antigen forming a dotted pattern in early myeloid cells and day 12 colony-forming units-spleen (CFU-S). Nuclear localization of p49 was further demonstrated by subcellular fractionation followed by Western blotting. We thus identified a nuclear protein that within the hematopoietic population is detected in hematopoietic precursor cells, predominates in early myeloid cells, and is reduced following differentiation. These properties imply that p49 might be involved in the regulation of hematopoietic cell growth or differentiation.

Acute Disease↗

PubMed1990

The combined effects of Il-3, GM-CSF and G-CSF on the in vitro growth of myelodysplastic myeloid progenitor cells.

The decreased or absent in vitro colony formation in response to single recombinant haematopoietic growth factors has been reported previously. Here we report on the effects of the combination of interleukin 3 (Il-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF) and the effect of the conditioned medium of the giant tumour cell line (GCT-CM) on the proliferation of myelodysplastic (MDS) marrow myeloid progenitor cells and normal bone marrow (NBM) controls. Colony growth was most effectively sustained by GCT-CM and G-CSF in normal bone marrow (NBM) cultures. GM-CSF and Il-3 were less effective in inducing myeloid granulocytic colony growth, whereas the effects of Il-3 and GM-CSF were found to be approximately additive. The number of NBM granulocytic colonies induced by G-CSF and GCT-CM stimulation were comparable, whereas this granulocyte colony stimulating activity could be neutralized by anti-G-CSF antibodies. In addition GCT-CM was found to contain burst promoting activity, which could be neutralized by anti-Il-3 antibodies. Il-3 did not enhance the G-CSF activity in NBM cultures. No additive effect of stimulation with the combination of Il-3 and GM-CSF was observed in MDS marrow cultures, suggesting that these growth factors act on an identical progenitor cell population in MDS. G-CSF stimulated the growth of significantly lower colony numbers than GCT-CM, in contrast to NBM cultures. The decreased granulocytic colony formation of MDS marrow cells could clearly be enhanced by co-stimulation with Il-3. These results suggest that MDS myeloid progenitor cells require the exposure to both a pluripotent colony stimulating factor, like Il-3, and a lineage specific factor, like G-CSF, for optimal proliferation.

Bone Marrow↗

PubMed2005

Increased eosinophil-lineage committed progenitors in the lung of allergen-challenged mice.

BACKGROUND: There is increasing evidence that hemopoietic progenitor cells may traffic from bone marrow to sites of allergen exposure in asthma and undergo in situ differentiation, contributing to ongoing airway inflammation. However, the isolation and detailed phenotyping of true CD34 + progenitors from lung tissue during an allergen-induced airway eosinophilia has not been performed. OBJECTIVE: We attempted to isolate and investigate the in vivo kinetics of hemopoietic progenitor cells and production of eosinophilopoietic mediators in the lung. METHODS: In a mouse model of allergic airway inflammation, cells were extracted from lung tissue by enzymatic digestion. Total (CD34 + 45 + ) and eosinophil lineage committed (CD34 + 45 + IL-5Ralpha + ) progenitors were enumerated by flow cytometry. Outcome measurements were made 2, 6, 12, 24, 48, and 72 hours and 7 and 14 days after allergen challenge. RESULTS: Compared with saline control, CD34 + 45 + progenitors were elevated between 6 and 48 hours ( P < .05), attenuated by 72 hours and subsequently increased by 14 days ( P > .05). CD34 + 45 + IL-5Ralpha + progenitors were transiently elevated at 6 hours ( P < .05) before a return to preallergen levels by 12 hours and a subsequent increase at 14 days ( P < .05). Bronchoalveolar lavage eosinophils were increased at 2 hours, peaking at 72 hours ( P < .00625) and declining by 14 days. Both IL-5 and eotaxin levels were increased by 2 hours, peaking at 12 hours ( P < .05) and 24 hours ( P < .05), respectively. CONCLUSION: We propose that the increase in CD34 + 45 + IL-5Ralpha + cells and the eosinophilopoietic mediators IL-5 and eotaxin in the lung after allergen exposure may promote in situ differentiation of eosinophils that contribute to ongoing allergic airway inflammation.

Animals↗

PubMed2005

Scopoletin induces apoptosis in human promyeloleukemic cells, accompanied by activations of nuclear factor kappaB and caspase-3.

Scopoletin (6-methoxy-7-hydroxycoumarin) is a phenolic coumarin and a member of the phytoalexins. In this study we investigated whether scopoletin caused apoptosis in HL-60 promyelocytic cells and, if so, by what mechanisms. We found that scopoletin induced apoptosis as confirmed by a characteristic ladder pattern of discontinuous DNA fragments in a dose-dependent manner. The signal cascade activated by scopoletin included the heterodimeric redox-sensitive transcription factor NF-kappaB, which exhibited an upregulation of nuclear factor-kappa B (NF-kappaB) translocation to the nucleus by increase of IkappaBalpha degradation. In addition, scopoletin activated caspase-3 as was evidenced by both the proteolytic cleavage of the proenzyme and increased protease activity. Activation of caspase-3 resulted in the cleavage of 116 kDa poly(ADP-ribose) polymerase (PARP) to 85 kDa cleavage product in time-and dose-dependent fashions. Prior treatment of the cells with pyrrolidine dithiocarbamate, a potent inhibitor of NF-kappaB activation, or Ac-DEVD-CHO, a specific caspase-3 inhibitor, prevented scopoletin-induced caspase-3 activation, PARP cleavage, and finally DNA fragmentation. Taken together, these results suggest that scopoletin induces NF-kappaB activation, which, in turn, causes activation of caspase-3, degradation of PARP, and eventually leads to apoptotic cell death in HL-60 cells.

Analysis of Variance↗

PubMed2005

The value of dot plot patterns and leukemia-associated phenotypes in AML diagnosis by multiparameter flow cytometry.

The immunophenotypic features in patients with acute myeloid leukemia (AML) were investigated at diagnosis using a wide antibody panel including progenitor-associated, myeloid and lymphoid markers in quadruple combinations. Analyzed were bone marrow samples from 37 adult and pediatric patients for exact identification of AML blasts according their localization on CD45/SSC dot plots and aberrant immunophenotypes in various subtype of AML. We found the localization of AML blasts on CD45/SSC dot plots, which in combination with immunophenotype profile of blasts allow discrimination of several AML subtypes (M0-M2, M3, M4/M5 and other types). In 27/37 AML patients (73%) at least one leukemia-associated phenotype (LAP) was found, two or more aberrancies coexisted in more than a half of them (78%). Asynchronous expression was the most frequent type of LAP (77.8%, 21/27) followed by coexpression of lymphoid-associated antigens, which occurred in 18/27 (66.7%) patients. Presented study showed that leukemic cells of each AML patient had a unique antigenic profile and could be discriminated from their normal counterparts based on typical light scatter profiles and aberrant antigen expression that could further be used for detection of minimal residual disease.

Acute Disease↗

PubMed1981

Surface antigens on normal and leukaemic human cells detected by monoclonal antibodies.

Surface antigens were analyzed on normal human marrow and chronic myeloid leukaemic cells using 4 monoclonal mouse anti-human antibodies. The fluorescence-activated cell sorter was used to quantify the binding of each antibody to different subpopulations of cells, and sorted fractions were cultured in agar-medium to assay for granulocyte-macrophage and eosinophil precursors. All cells in the granulocyte series including colony-forming cells bound a similar quantity of an antibody to the human leucocyte common antigen. This antibody did not bind to cells in the erythroid series. A monoclonal antibody to antigen present on brain, lymphocytes and granulocytes (and almost certainly homologous to the W3/13 antigen of the rat) bound to the cells in the order: blast greater than promyelocytes and myelocytes greater than granulocytes. The third monoclonal antibody was directed against a determinant of the leucocyte common antigen present predominantly on B lymphocytes and absent from the myeloid series. The fourth antibody, directed against the human homologue of Thy-1, reacted with less than 1% of marrow cells, none of which appeared to be granulocyte or eosinophil progenitors. The leucocoyte common antigen and the brain-lymphocyte-granulocyte-antigen were also present on colony- and cluster-forming cells from a patient with chronic myeloid leukemia. Using the low angle and wide angle light scatter properties of CML blood cells, 7-fold enrichment was obtained for progenitor cells from chronic myeloid leukaemia. With the monoclonal antibodies up to 4-fold enrichment was obtained.

Animals↗

PubMed2004

Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development.

The cerebellum consists of a highly organized set of folia that are largely generated postnatally during expansion of the granule cell precursor (GCP) pool. Since the secreted factor sonic hedgehog (Shh) is expressed in Purkinje cells and functions as a GCP mitogen in vitro, it is possible that Shh influences foliation during cerebellum development by regulating the position and/or size of lobes. We studied how Shh and its transcriptional mediators, the Gli proteins, regulate GCP proliferation in vivo, and tested whether they influence foliation. We demonstrate that Shh expression correlates spatially and temporally with foliation. Expression of the Shh target gene Gli1 is also highest in the anterior medial cerebellum, but is restricted to proliferating GCPs and Bergmann glia. By contrast, Gli2 is expressed uniformly in all cells in the developing cerebellum except Purkinje cells and Gli3 is broadly expressed along the anteroposterior axis. Whereas Gli mutants have a normal cerebellum, Gli2 mutants have greatly reduced foliation at birth and a decrease in GCPs. In a complementary study using transgenic mice, we show that overexpressing Shh in the normal domain does not grossly alter the basic foliation pattern, but does lead to prolonged proliferation of GCPs and an increase in the overall size of the cerebellum. Taken together, these studies demonstrate that positive Shh signaling through Gli2 is required to generate a sufficient number of GCPs for proper lobe growth.

Animals↗

PubMed1995

Proliferative response of human marrow myeloid progenitor cells to in vivo treatment with granulocyte colony-stimulating factor alone and in combination with interleukin-3 after autologous bone marrow transplantation.

We have recently reported that the hematologic recovery of patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) undergoing autologous bone marrow transplantation (BMT) is significantly faster when recombinant human interleukin-3 (rhIL-3) is combined with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in comparison with patients receiving G-CSF alone. In this paper, we studied the kinetic response and concentration of BM progenitor cells of 17 patients with lymphoid malignancies submitted to autologous BMT and treated with the G-CSF/IL-3 combination. The results were compared with those of five lymphoma patients receiving the same pretransplant conditioning regimen followed by G-CSF alone. rhG-CSF was administered as a single subcutaneous (sc) injection at the dose of 5 micrograms/kg/d from day 1 after reinfusion of autologous stem cells; rhIL-3 was added from day 6 at the dose of 10 micrograms/kg/d sc (overlapping schedule). In both groups (G-CSF- and G-CSF/IL-3-treated patients), cytokine administration was discontinued when the absolute neutrophil count (ANC) was >0.5 x 10(9)/L of peripheral blood (PB) for 3 consecutive days. After treatment with the CSF combination, the percentage of marrow colony-forming units-granulocyte/macrophage (CFU-GM) and erythroid progenitors (BFU-E) in S phase of the cell cycle increased from 9.3 +/- 2% to 33.3 +/- 12% and from 14.6 +/- 3% to 35 +/- 6%, respectively (p < 0.05). Similarly, we observed an increased number of actively cycling megakaryocyte progenitors (CFU-MK and BFU-MK). Conversely, G-CSF augmented the proliferative rate of CFU-GM (22.6 +/- 0.6% compared to a baseline value of 11.5 +/- 3%; p < 0.05) but not of BFU-E, CFU-MK, or BFU-MK, and the increase of S-phase CFU-GM was significantly lower than that observed in the posttreatment samples of patients receiving IL-3 in addition to G-CSF. The frequency of hematopoietic precursors in the BM, expressed as the number of colonies formed per number of cells plated, was unchanged or slightly decreased in both groups of patients. Because of the increase in marrow cellularity, however, a significant augmentation of the absolute number of both CFU-GM (3605 +/- 712/mL BM vs. 2213 +/- 580/mL; p < 0.05) and BFU-E (4373 +/- 608/mL vs. 3027 +/- 516/mL; p < 0.05) was reported after treatment with G-CSF/IL-3 but not G-CSF alone. Similarly, administration of the cytokine combination resulted in a higher number of CD34+ cells/mL BM, and their concentration was significantly greater than that observed in the posttreatment samples of G-CSF patients. Finally, we investigated the responsiveness to CSFs, in vitro, of highly enriched CD34+ cells, collected after priming with G-CSF in vivo (i.e., after 5 days of G-CSF administration). Our results demonstrated that pretreatment with G-CSF modified the response of BM cells to subsequent stimulation with additional CSFs. The results presented in this paper indicate that in vivo administration of two cytokines increases the proliferative rate and concentration of BM progenitor cells to a greater degree than G-CSF alone. These results support the role of growth factor combinations for accelerating hematopoietic recovery after high-dose chemotherapy.

Bone Marrow Cells↗

PubMed2004

Lipoteichoic acid derived from Enterococcus faecalis modulates the functional characteristics of both normal peripheral blood leukocytes and native human acute myelogenous leukemia blasts.

OBJECTIVES: Several case reports have described complete hematological remissions for patients with otherwise untreated acute myelogenous leukemia (AML) who receive hematopoietic growth factor therapy during complicating bacterial infections. This may be caused by indirect cytokine effects, but direct effects of infecting agents on the malignant cells are also possible because bacterial molecules can bind to specific receptors expressed by normal and malignant leukocytes. Lipoteichoic acid (LTA) is a cell wall component of gram-positive bacteria, and it can activate normal immunocompetent cells through binding to specific cell membrane receptors. METHODS: We investigated effects of LTA derived from Enterococcus faecalis on in vitro cultured (i) normal peripheral blood mononuclear cells (PBMC); (ii) remaining T cells derived from patients with hematologic malignancies and chemotherapy-induced leukopenia; and (iii) native human AML cells. RESULTS: Increased interleukin 1beta (IL1beta) and IL8 release by in vitro cultured normal PBMC was observed after stimulation with LTA at concentrations > or =5 microg/mL; these levels were lower than for lipopolysaccharide (LPS)-stimulated cells and LTA antagonized LPS-induced cytokine release by normal PBMC. In most cases LTA did not alter T-cell proliferation for patients with chemotherapy-induced leukopenia. The LTA effects on AML blasts were investigated for 62 consecutive patients. LTA altered either cytokine (granulocyte-macrophage colony-stimulating factor + stem cell factor + IL3)-dependent proliferation or the release of IL1beta/IL8 for 23 patients; the effects were divergent but increased proliferation/cytokine levels were most commonly observed. CONCLUSION: The LTA derived from E. faecalis can modulate the functional characteristics of normal leukocytes and native human AML blasts.

Adult↗

PubMed1987

Growth of murine bone marrow under various oxygen conditions in media buffered with HEPES.

Increased plating efficiencies were observed for marrow granulocyte-macrophage precursor cells (CFU-gm) cultured in an experimental system at reduced gas-phase oxygen concentrations. However, only a small component of this increase was attributable to decreased oxygen. The changed media buffering system was the more dominant factor contributing to increased plating efficiency, suggesting that other factors in addition to a reduction in oxygen may influence clonogenicity.

Animals↗

PubMed1990

Short term benzene exposure provides a growth advantage for granulopoietic progenitor cells over erythroid progenitor cells.

Because chronic benzene exposure is associated with acute myeloblastic leukemia and other myeloproliferative disorders, we sought to determine whether short-term benzene exposure provides a growth advantage for granulopoietic elements over erythropoietic elements. Groups of male DBA/2J mice were exposed to 0, 10, 30, or 100 ppm benzene (6 h/day for 5 days). One day and 5 days after the benzene exposures, the numbers of the two most primitive erythroid progenitor cells (BFU-E and CFU-E) and the numbers of the most primitive granulocytic progenitor cells (GM-CFU-C) were assessed. Additional groups of mice were given hemolytic doses of phenylhydrazine (PHZ) during the 5 days of benzene exposure, while other groups of mice were given PHZ during the 5 days of recovery from benzene exposure. These experiments were designed to determine the effects of benzene exposure on progenitor cell numbers during periods of markedly heightened erythropoiesis. The results demonstrate that short-term benzene exposure does induce a growth advantage for granulocytic cells in both the bone marrow and spleen of exposed mice. Moreover, a benzene-induced shift toward granulopoiesis is observed even in those mice treated with a powerful erythropoietic stimulus. These effects disappear 5 days after cessation of benzene exposure in the bone marrow but persist in the spleen of mice treated with phenylhydrazine.

Animals↗

PubMed2005

Curcuma longa extract protects against gastric ulcers by blocking H2 histamine receptors.

Curcuma longa has been commonly used as a traditional remedy for a variety of symptoms such as inflammation, gastritis and gastric ulcer. When C. longa extract was administered per os to pylori-ligated rat stomachs, it reduced gastric acid secretion and protected against the formation of gastric mucosal lesions. We therefore tested whether C. longa extract inhibits gastric ulcers by blocking the H(2) histamine receptor. Dimaprit, a H(2) histamine receptor agonist, induced intracellular cAMP production in U937 and HL-60 promyelocytes. Pretreatment with C. longa extract significantly blocked dimaprit-induced cAMP production in a concentration dependent manner, but had no effect on the elevation of cAMP levels triggered by isoproterenol-induced beta(2)-adrenoceptor activation in U937 cells. To identify the active component(s) of C. longa extract, we sequentially fractionated it by extraction with ethyl acetate, n-butanol and water. We found that the ethyl acetate extract showed the most potent H(2)R antagonistic effect against dimaprit-induced cAMP production. However, curcumin, a major component of C. longa extract, showed no H(2)R blocking effect. C. longa ethanol extract and ethylacetate extract also blocked the binding of [(3)H]-tiotidine to membrane receptors on HL-60 cells. These findings suggest that the extract from C. longa specifically inhibits gastric acid secretion by blocking H(2) histamine receptors in a competitive manner.

Acetates↗

PubMed1992

Effects of tumor necrosis factor-alpha on normal feline hematopoietic progenitor cells.

The effects of tumor necrosis factor-alpha (TNF-alpha) on feline bone marrow hematopoietic progenitors were evaluated by exposing bone marrow mononuclear cells from specific pathogen-free cats to different concentrations of TNF-alpha (ranging from 50 to 800 pg/ml) for 2 h before plating for clonal assays of colony-forming units. TNF-alpha caused a dose-dependent suppression of feline erythroid colony-forming units (CFU-E) and erythroid burst-forming units (BFU-E), whereas granulocyte-macrophage colony-forming units (CFU-GM) were minimally affected. TNF-alpha concentrations as low as 200 pg/ml significantly inhibited growth of erythroid progenitors. Addition of polyclonal rabbit anti-TNF-alpha antibodies completely neutralized the suppressive effect of TNF-alpha on erythroid progenitors. At higher concentrations of TNF-alpha (800 pg/ml), 35% of CFU-E and 21% of BFU-E still survived, indicating that some erythroid progenitors are not sensitive to a single exposure of TNF-alpha in vitro. These results suggest that TNF-alpha may play a role in regulating hematopoiesis in cats and may be involved in the pathogenesis of erythroid aplasia in cats infected with feline leukemia virus.

Animals↗

PubMed1991

Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth.

Previous studies have shown that 2-chloro-2'-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony-forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood. Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were used for our investigations. The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming cells in a dose-dependent manner, correlating with maturation stage in that the immature progenitor cells are more sensitive to this drug. Furthermore, our studies suggest that a sequence of metabolic events previously described for lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of 48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to be high in lymphocytes, but low in granulocytes. However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that other factors such as modulation of the effect of CdA by the ambient levels of other deoxynucleosides might influence the apparent sensitivity of myeloid cells.

2-Chloroadenosine↗

PubMed1994

The in vitro and in vivo effect of recombinant interferon alpha-2a on circulating haemopoietic progenitors in polycythaemia vera.

In four patients with polycythaemia vera (PV) who received interferon alpha (IFN-alpha) (3 MU subcutaneously three times a week) for 5 months, peripheral blood levels of granulocyte-macrophage colony-forming units and erythroid burst-forming units were assessed monthly. Circulating progenitors significantly decreased throughout the treatment period. Moreover, we observed an inhibitory activity of IFN-alpha on haemopoietic progenitor cells (HPC) from patients with PV in vitro. The data presented confirm previous research which has shown an inhibitory effect of IFN-alpha on HPC from patients with myeloproliferative disorders. Significant improvement in the patients' clinical and haematological conditions should encourage larger studies on IFN-alpha administration in PV patients.

Aged↗

PubMed1996

Selective engraftment of the granulocyte compartment after allogeneic bone marrow transplantation in a patient with severe aplastic anemia.

PURPOSE: We present a patient with severe aplastic anemia who had partial engraftment with full chimerism after allogeneic bone marrow transplantation from an HLA identical sibling. PATIENTS AND METHODS: A 3-year-old girl with severe aplastic anemia (SAA) received a bone marrow transplantation (BMT) from an HLA identical brother 9 months after her diagnosis. Before BMT she was red blood cell tranfusion dependent, had an absolute neutrophil count (ANC) of 1,000-1,500 x 10(9)/1 and a platelet count of 15-19,000 x 10(9)/1. She was conditioned with 800 cGy total body irradiation (TBI) and cyclophosphamide and received 3X10(8) nucleated cells/kg. RESULTS: She reached an ANC of 1500 x 10(9)/1 on day +35 but her reticulocyte and platelet counts did not recover. A bone marrow aspirate and biopsy post BMT showed hypoplasia with marked decrease in megakaryocyte and red blood cell precursors. The granulocyte compartment showed a left shift with predominance of promyelocytes and myelocytes. The karyotype showed full chimerism (46,XY) with no 46,XX metaphases. CONCLUSION: This case illustrates the possibility of a bone marrow microenvironment defect as the cause of SAA.

Anemia, Aplastic↗

PubMed1993

Direct effects of 13-cis and all-trans retinoic acid on normal bone marrow (BM) progenitors: comparative study on BM mononuclear cells and on isolated CD34+ BM cells.

The effects of both 13-cis-and all-trans retinoic acid (RA) on colony formation of normal bone marrow (BM) progenitors were investigated in semi-solid (methylcellulose) assays, using either isolated CD34+ cells or BM mononuclear cells. Single cell liquid cultures were performed to further discriminate between direct and indirect effects. RA action results in significant decrease of colony forming units (CFUs). This effect is more pronounced starting from CD34+ progenitors than starting from total BM. This overall decrease in CFUs is due to selective inhibition of CFU-M (macrophage) and erythroid colonies (BFU-E). At the single cell level the CFU-M inhibition is confirmed with--in addition--a significant inhibition of CFU-GM (granulocyte-macrophage) and a marked stimulation of CFU-G (granulocyte)s. Both retinoids exert the above-mentioned effects. All-trans RA, however, is effective at a tenfold lower concentration (10(-7)M) than 13-cis RA (10(-6)M). Results on CD34+ BM fractions (substantially reduced in accessory cells) demonstrate that the described effects can probably be attributed to the direct action of RA on these progenitors; single progenitor (CD34+) cell liquid cultures further prove this point.

Antigens, CD↗