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V Gattei

Publications and source records attributed to V Gattei.

At least 37 records · Page 2Linked to original sources
PubMed1997

The role of eosinophils in the pathobiology of Hodgkin's disease.

BACKGROUND: Even though the presence of a prominent tissue eosinophilia represents a common histopathologic feature of Hodgkin's disease (HD), eosinophils have been mainly regarded as 'innocent' bystanders recruited and activated during the cellular reaction typical of HD. To evaluate the putative role of eosinophils or eosinophil-derived cytokines on tumor-cell regulation in HD, we have analyzed these cells for the functional expression of surface ligands (L) of the tumor necrosis factor (TNF) superfamily, whose specific receptors are known to transduce proliferation signals at the surface of Hodgkin (H) and Reed-Sternberg (RS) cells. MATERIALS AND METHODS: Eosinophils from peripheral blood of healthy donors and patients with HD, primary hypereosinophilic syndrome (HES), or secondary hypereosinophilia (HE), were purified by density gradient centrifugation and immunomagnetic depletion of residual granulocytes. RESULTS: By immunostaining and mRNA analysis, we were able to show that eosinophils from normal donors and patients with HD, HES, and HE express a number of receptors and ligands of the TNF superfamily, including CD40, CD40L, CD30L, CD95/Fas, CD95/FasL and 4-1BB. In addition, we provide evidence that cytokines regulating eosinophil proliferation and activation, i.e., interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor, are able to enhance the cellular density of several TNF superfamily ligands and/or receptors at the surface of cultured eosinophils. Finally, we have shown that native CD40L and CD30L at the surface of purified eosinophils are functionally active and able to transduce proliferative signals on CD40+ and CD30+ target cells, including cultured H-RS cells. CONCLUSIONS: Our data suggest that eosinophils may act as important elements in the pathology of HD by providing cellular ligands for TNF-superfamily receptors (CD40, CD30, CD95/Fas) able to transduce proliferation and antiapoptotic signals at the surface of H-RS cells. The presence on eosinophils of receptors for TNF ligands expressed by activated T cells (i.e., OX40L, FasL, CD40L, 4-1BBL), also suggest that eosinophils may contribute to the deregulated network of interactive signals between H-RS cells, T cells, and other surrounding reactive cells.

Antigens, Neoplasm↗
PubMed1997

Human granulocyte-macrophage colony-stimulating factor supports the clonogenic growth of B-lineage acute lymphoblastic leukemias expressing myeloid antigens.

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-6 on clonogenic growth of blast-cell progenitors from 19 immunologically defined CD10-positive B-lineage acute lymphoblastic leukemias (ALL) coexpressing (My+ALLs) or not (My-ALLs) myeloid antigens have been studied. Our results demonstrate that GM-CSF was able to support the clonogenic growth of blast cells from My+ALLs, being totally ineffective on My-All samples. Accordingly, both alpha and beta chains of GM-CSF receptor (R) were expressed by My+ALL blasts, as investigated by reverse-transcriptase polymerase chain reaction (RT-PCR). Colony cells from GM-CSF-stimulated My+ALL cultures displayed the same immunophenotype as primary leukemic cells at diagnosis (CD10+, CD19+, CD22+), and retained the expression of myeloid-associated antigens and of GM-CSF-R transcripts. Moreover, My+ALL blasts showed a preferential sensitivity to the growth-promoting activity of IL-3 and IL-6, as compared with My-ALL cells. In addition to rearrangements of the JH region of immunoglobulin genes, My+ALL cells showed aberrant rearrangements of gamma (three cases) and beta (two cases) T-cell receptor genes, as well as of bcr sequences (three cases). Our data, showing an unexpected cross-lineage response of My+ALLs to GM-CSF, and their preferential stimulation by IL-3 and IL-6, as compared with My-ALLs, further support the concept that My+ALLs represent a separate entity with unique biological features.

Adolescent↗
PubMed1996

Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line.

The presence of a prominent tissue eosinophilia represents a typical histopathologic hallmark of Hodgkin's disease (HD). To evaluate the putative role of eosinophils on tumor cell regulation in HD, we have analyzed these cells for the functional expression of CD30 ligand (CD30L), a surface molecule able to transduce CD30-mediated proliferation signals on Hodgkin's (H) and Reed-Sternberg (RS) cells. The results demonstrate that circulating and tissue eosinophils from normal donors and patients with HD or hypereosinophilic syndrome (HES), display CD30L mRNA and express CD30L protein, as shown by immunostaining with a specific monoclonal antibody (M80) and with a biotinylated soluble CD30-Fc fusion protein. The surface density of CD30L on eosinophils from HD and HES patients was remarkably higher compared with healthy donors, probably reflecting a cytokine-mediated upregulation in these pathologic conditions. Accordingly, we provide evidence that cytokines regulating eosinophils proliferation and activation, ie, interleukin-5 (IL-5), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF), are able to enhance the cellular density of CD30L on purified eosinophils from normal subjects. Finally, we show that native CD30L on human eosinophils is a functionally active surface structure able to transduce proliferative signals on CD30+ target cells, including cultured H-RS cells. Our data suggest that eosinophils may not merely represent innocent bystanders, but rather act as important elements in the pathology of HD by contributing to the deregulated network of CD30/CD30L-mediated interactive signals between H-RS cells and surrounding reactive cells.

CD30 Ligand↗
PubMed1996

CD30 ligand expression in nonmalignant and Hodgkin's disease-involved lymphoid tissues.

The CD30 ligand (CD30L) is a type II transmembrane glycoprotein of the tumor necrosis factor ligand superfamily. Recent cloning of CD30L has enabled studies to explore its function and tissue distribution. For instance, recombinant CD30L has been shown to co-stimulate T cells and to act as mitogen for Hodgkin's disease (HD)-derived cell lines. The counter-receptor for CD30L, ie, CD30, is a type I cytokine receptor that is highly expressed by activated T cells, Hodgkin and Reed-Sternberg (H-RS) cells, and anaplastic large cell lymphoma cells. In the present study, recombinant membrane-bound and soluble human CD30L were instrumental to raise a monoclonal antibody (M80) recognizing membrane-bound CD30L on transfected and native cells. With this reagent, a panel of cultured lymphoma-derived cell lines as well as primary normal, reactive, and HD-involved lymphoid tissues were examined for expression of CD30L by immunostaining and flow cytometry. In reactive lymphnodes and tonsils, CD30L was expressed by a small subset of lymphoid cells, histiocytes, and granulocytes. Higher levels of CD30L expression were noted in HD lesions among bystander cells; ie, T cells and granulocytes that surrounded H-RS cells. Native CD30L displayed at the cell surface was functionally active as shown by the ability of fixed granulocytes to interact with CD30+ cell lines. Moreover, CD30L was detectable, although to a lower staining intensity, in primary H-RS cells of all HD tissues investigated regardless of the histological subtype and the phenotype of H-RS cells (ie, CD30+/CD40+ versus CD30-/CD40+). Co-expression of CD30 and CD30L that was seen on H-RS cells of all, except the CD30- nodular lymphocyte predominant, subtypes of HD may point to the use of this pair of molecules in paracrine and/or autocrine mitogenic cell interactions. Monoclonal antibody M80 may thus represent a useful tool for studying CD30L expression on cultured cell lines and primary cells from normal, reactive, and malignant tissues.

Antibodies, Monoclonal↗
PubMed1996

Human osteoclasts and preosteoclast cells (FLG 29.1) express functional c-kit receptors and interact with osteoblast and stromal cells via membrane-bound stem cell factor.

Bone remodeling requires cooperation between osteoclasts and other specialized or accessory bone cell populations by mechanisms that have not been completely elucidated. Here we describe the expression and functional role of the proto-oncogene c-kit and of its specific ligand stem cell factor (SCF) on human osteoclasts, osteoblasts, and stromal cells derived from different sources. Our results indicate that primary osteoclasts in imprints of metaphyseal bone and giant cell tumors (GCTs) of bone, as well as a bone marrow-derived preosteoclast cell line of human origin (FLG 29.1), expressed immunodetectable c-kit protein. In contrast, tissue osteoclasts did not react with anti-SCF antibodies, and barely detectable levels of SCF mRNA and protein were found in FLG 29.1 cells. Conversely, a strong expression of membrane bound-SCF was found in primary cultured bone marrow stromal cells, in a stromal cell line (C433) derived from the mononuclear component of GCT of bone, and in a human cell line with osteoblast features (Saos-2). FLG 29.1 preosteoclast cells displayed about 29,000 binding sites/cell of a single class of high affinity c-kit receptors (Kd 6.12 x 10(-10) mol/L) with a molecular weight of about 140 kDa, along with a structurally normal c-kit mRNA. Proliferation of FLG 29.1 preosteoclast cells was stimulated by exogenous SCF, indicating that c-kit was capable of transducing growth signals. Finally, in vitro adhesion of FLG 29.1 cells to primary bone marrow stromal cells, GCT-derived stromal cells (C433), and Saos-2 osteoblast cells was significantly inhibited by an excess of soluble SCF or by monoclonal antibodies recognizing SCF binding sites on the c-kit receptor. These results indicate that c-kit is constitutively expressed on human osteoclasts and that it may be directly implicated in cell contact-dependent interaction of osteoclasts with other specialized or accessory cell populations of the bone microenvironment. Our observations suggest a role for SCF in human diseases characterized by abnormal bone resorption and remodeling.

Bone Marrow↗
PubMed1995

The expression of CD26 and CD40 ligand is mutually exclusive in human T-cell non-Hodgkin's lymphomas/leukemias.

CD26 and CD40 ligand (CD40L) are surface molecules on human activated T lymphocytes that play a critical role in the regulation of lymphopoiesis. Both molecules are expressed on a restricted fraction of human T-cell non-Hodgkin's lymphomas (NHL)/leukemias; however, little is known about their functional and/or clinical significance in these disorders. In this study, the pattern of expression of CD40L was compared with that of the CD26 molecule. A series of 67 human T-cell NHL/leukemias and a panel of leukemia/lymphoma T-cell lines were evaluated by immunohistochemistry, flow cytometry, and RNA studies. The overall frequency of CD26+ and CD40L+ samples was rather similar (25/67 [37%] v 18/67 [27%]). However, the majority of CD26-expressing cases clustered in the lymphoblastic lymphomas (LBL)/T-acute lymphoblastic leukemias (ALL; 12/23) and CD30+ anaplastic large-cell (ALC) lymphomas (5/8), whereas CD40L+ lymphomas included a large fraction of mycosis fungoides (11/21 [52%]). CD26 and CD40L coexpression was found only in 2 myocosis fungoides cases and 1 small lymphocytic lymphoma. Thus, the expression of the two antigens was mutually exclusive in almost all T-cell lymphomas/leukemias. Accordingly, lymphoma cell lines expressed either one of the molecules or the relative amounts of CD26 and CD40L were inversely proportional. In contrast, reactive T lymphocytes from patients with non-neoplastic T-cell expansions and in vitro activated CD3+ or CD4+ normal T cells were found to coexpress CD40L and CD26. Results of a multivariate analysis showed that the expression of CD26 in T-cell LBL/ALL patients was associated to a worse outcome in terms of survival, as compared with patients with CD26- tumors (P < or = .0001). Based on our results, it can be concluded that, (1) as opposed to activated or reactive normal T cells, the expression of CD26 and of CD40L is mutually exclusive in human T-cell lymphomas/leukemias; (2) expression of CD26 is restricted to aggressive pathologic entities, such as T-cell LBL/ALL and T-cell CD30+ ALC lymphomas, whereas CD40L is expressed on slow progressing diseases such as mycosis fungoides; and (3) within the T-cell LBL/ALL group of tumors, CD26 may identify a subset of poor prognosis patients.

Adolescent↗
PubMed1995

Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells.

Proline-rich homeobox (Prh) is a novel human homeobox-containing gene recently isolated from the CD34+ cell line KG-1A, and whose expression appears mainly restricted to hematopoietic tissues. To define the pattern of Prh expression within the human hematopoietic system, we have analyzed its constitutive expression in purified cells obtained from normal hematopoietic tissues, its levels of transcription in a number of leukemia/lymphoma cell lines representing different lineages and stages of hematolymphopoietic differentiation, and its regulation during in vitro maturation of human leukemic cell lines. Prh transcripts were not detected in leukemic cells of T-lymphoid lineage, irrespective of their maturation stage, and in resting or activated normal T cells from peripheral blood and lymphoid tissues. In contrast, high levels of Prh expression were shown in cells representing early stages of B lymphoid maturation, being maintained up to the level of circulating and tissue mature B cells. Terminal B-cell differentiation appeared to be conversely associated with the deactivation of the gene, since preplasmacytic and plasmocytoma cell lines were found not to express Prh mRNA. Prh transcripts were also shown in human cell lines of early myelomonocytic, erythromegakaryocytic, and preosteoclast phenotypes. Prh expression was lost upon in vitro differentiation of leukemic cell lines into mature monocyte-macrophages and megakaryocytes, whereas it was maintained or upregulated after induction of maturation to granulocytes and osteoclasts. Accordingly, circulating normal monocytes did not display Prh mRNA, which was conversely detected at high levels in purified normal granulocytes. Our data, which show that the acquisition of the differentiated phenotype is associated to Prh downregulation in certain hematopoietic cells but not in others, also suggest that a dysregulated expression of this gene might contribute to the process of leukemogenesis within specific cell lineages.

B-Lymphocytes↗
PubMed1995

Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin's disease cell lines.

CD40 is a member of the nerve growth factor receptor family, showing a significant homology to the Hodgkin's disease (HD)-associated antigen CD30 and is capable of transduce growth signals in a number of cell types. A series of 312 lymphoma samples, including 139 cases of HD, 32 cases of CD30+ anaplastic large cell (ALC) lymphomas, 141 cases of other non-Hodgkin's lymphomas (NHLs), and a panel of HD- or NHL-derived cell lines, were evaluated for CD40 expression by immunostaining of paraffin embedded sections, cell smears and flow cytometry. CD40 was strongly expressed with a highly distinct pattern of staining on Reed-Sternberg (RS) cells and variants in 100% (139/139) of HD cases, irrespective of their antigenic phenotype (T, B, non T-non B) and histologic subtype of HD. Conversely, CD40 was immunodetected on only one third (12/32; 37%) of ALC lymphoma cases and on 105 of 127 B-cell NHLs. The relative cell density of CD40 on HD cell lines (L-428, KM-H2, HDLM-2) as assessed by flow cytometry was significantly higher than on all other lymphoma cells analyzed. Engagement of CD40 by its soluble ligand (CD40L) enhanced both clonogenic capacity and colony cell survival of HD cell lines. Such effect was potentiated by interleukin-9 costimulation in KM-H2 cells. Finally, we have shown that in vitro rosetting of activated CD4+ T cells to HD cells (L-428) is mediated in part by the CD40/CD40L adhesion pathway. Our data indicate that CD40 is a useful antigen for immunodetection and identification of tumor cells in all subtypes of HD, and suggest that it may play a role in the regulation of RS cell expansion and the contact-dependent interactions of these cells with cytokine-producing T lymphocytes.

Animals↗
PubMed1995

In vitro structural and functional relationships between preosteoclastic and bone endothelial cells: a juxtacrine model for migration and adhesion of osteoclast precursors.

The role of vascularization in the process of bone resorption has not been clarified. The interactions between vascular endothelium and osteoclast progenitors were analyzed using clonal cell lines of bone-derived endothelial and preosteoclastic cells. Insulin-like growth factor I is a major chemotactic stimulator of preosteoclastic cell migration mediated by bone endothelial cells. Osteoclast precursors rapidly adhered to bone endothelial monolayers. This phenomenon appeared to be cell-specific and mediated through the binding of vitronectin and fibronectin receptors to fibronectin. In addition, direct contact with bone endothelial cells induced osteoclast progenitors to differentiate into more mature elements, with the tendency to cluster together to form large multinucleated cells. These findings demonstrated specific in vitro interactions between bone endothelial cells and osteoclast progenitors, offering a new model for understanding the molecular mechanisms which direct the processes of osteoclast recruitment and ontogeny.

Animals↗
PubMed1994

Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's disease and CD30+ anaplastic large cell lymphomas.

The product of the proto-oncogene c-kit is a transmembrane receptor protein that plays an important role in the regulation of normal and neoplastic hematopoiesis via the interaction with its specific ligand termed stem cell factor. To examine whether c-kit product is possibly involved in the pathogenesis of human lymphomas, we analyzed the expression of the c-kit protein in neoplastic cells from a variety of lymphoid tumors by immunostaining of lymph node frozen sections with the 17F11 antibody, detecting an extracellular epitope of the c-kit receptor, and of c-kit RNA by Northern blot hybridization. Of 24 nonHodgkin's lymphomas (NHL) of B- and T-cell phenotype, none expressed immunodetectable c-kit protein that was also not evidenced in lymphoid cells of reactive lymph nodes and normal tonsils. In contrast, c-kit protein was expressed by Reed-Sternberg cells and their mononuclear variants from 11 of 21 Hodgkin's disease (HD) cases, and in tumor cells from 11 of 16 cases of CD30+ anaplastic large cell lymphoma (ALCL). c-kit specific mRNA was also detected in lymph node tissues from HD and ALCL cases but not in neoplastic tissues from NHL other than ALCL. In addition, c-kit/CD30+ tumor cells were evidenced by flow cytometry in a patient displaying massive bone marrow involvement by ALCL. With the exclusion of lymphocyte predominance cases of HD that resulted c-kit expression and the other histologic subtypes of HD or the immunologic phenotype of tumor cells (B, T, nonB-nonT) in both HD and ALCL. The highly restricted expression of the c-kit product among human lymphomas to HD and ALCL provides a further biologic link between these two closely related lymphoma entities.

Hodgkin Disease↗
PubMed1993

5-Aza-2'-deoxycytidine (Decitabine) induces trilineage response in unfavourable myelodysplastic syndromes.

The preliminary results of a disease-oriented phase I-II study aimed at evaluating the clinical activity of 5-aza-2'-deoxycytidine (Decitabine) in patients affected by advanced myelodysplastic syndromes (MDS) are reported. Two patients affected by refractory anemia with excess of blasts (RAEB) and eight with RAEB in transformation (RAEB-T) were treated with Decitabine at a daily dose of 45 mg/m2, divided into three 4 h infusions for 3 days (six patients) or as continuous infusion of 50 mg/m2 for 3 days (four patients). Treatment with Decitabine resulted in a significant increase in circulating neutrophils, platelets, and hemoglobin with respect to pretreatment values in over 50% of patients. These changes were accompanied by the improvement of the marrow myeloid relative differentiation index (median fivefold increase in the whole group of patients) and of the myeloid to erythroid cell ratio (median twofold increase) in most of the patients. In four out of ten patients a complete normalization of peripheral blood (PB) and bone marrow (BM) picture (complete hematologic response) was obtained. The evaluation of the percentage of CD34-positive BM cells showed a slow but progressive reduction of early leukemic progenitors in most of the patients. A transient slight BM hypoplasia was obtained in less than 50% of patients while a severe marrow aplasia was never observed in our group of MDS patients during treatment with Decitabine. Extra-hematological toxicity was very mild in all the patients. The preliminary results of our study indicate that Decitabine is able to induce trilineage hematological responses in advanced MDS patients along with a stable normalization of the PB and BM picture in some of the subjects. Decitabine appears an active agent in advanced MDS and this deserves careful investigation in this heterogeneous group of disorders.

Aged↗
PubMed1993

Pilot study of 5-aza-2'-deoxycytidine (Decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results.

5-Aza-2'-deoxycytidine (Decitabine) is a new cytosine analog with potent antileukemic activity and able to induce in vitro gene activation and cellular differentiation by a mechanism probably involving DNA hypomethylation. The aim of this pilot study was to evaluate the efficacy and the toxicity of Decitabine, used as single induction agent, in the treatment of poor prognosis acute myeloid leukemia (AML) patients, and to explore its mechanism of action. A total of 12 patients were treated with Decitabine at 90-120 mg/m2 as a four hour intravenous infusion, three times daily for three consecutive days every four to six weeks. A minimum of two courses were required for response evaluation and to consider a patient as therapeutic failure. A total of 10/12 patients were fully evaluable for response; three patients achieved a complete remission (CR) and one a partial remission (PR). Extra-hematological toxicity was generally mild. As for the mechanism of action, both a differentiation induction effect and a cytotoxic mechanism have been observed. In particular, CRs and PRs were probably obtained through the induction of leukemia cell differentiation as shown by the kinetic of remission and immunotyping studies. The preliminary results of this ongoing study suggest that Decitabine may have a prominent role in the treatment of those AML patients with poor general conditions and/or advanced age.

Aged↗
PubMed1993

In vitro and in vivo effects of 5-aza-2'-deoxycytidine (Decitabine) on clonogenic cells from acute myeloid leukemia patients.

5-Aza-2'-deoxycytidine (Decitabine) is an analog of deoxycytidine now entering clinical trials in acute myeloid leukemia (AML) owing to a defined antileukemic activity mediated at least in part by DNA hypomethylation, altered gene expression, and induction of cell differentiation. In the present study, we examined the relationship between the in vitro sensitivity to Decitabine of blast progenitors and the clinical outcome, in nine AML patients treated in vivo with Decitabine within a phase II trial carried out at two different institutions. Leukemic blast progenitors in acute myeloid leukemia (AML) undergo terminal divisions giving rise to colonies in methylcellulose. The self-renewal capacity of blast progenitors is conversely reflected by a secondary methylcellulose assay after exponential growth of clonogenic cells in suspension cultures. Three out of four patients, in which clonogenic cells in methylcellulose were strongly suppressed by Decitabine and clonogenic growth of blasts cultured in suspension was only slightly affected, failed on Decitabine treatment in vivo. Two subjects, whose blast progenitors in suspension culture were significantly inhibited by Decitabine, obtained a positive hematological response (complete or partial remission, CR or PR) and an additional patient showing a similar in vitro pattern died in induction with an hypoplastic marrow without morphological evidence of persistant leukemia. Interestingly two patients displaying an unfavourable in vitro pattern (i.e. a minor suppression of self-renewal mitoses as evinced from suspension cultures) achieved a hematological response (CR and PR) upon in vivo therapy with Decitabine. The in vitro response to Decitabine of clonogenic progenitors from both these patients shifted to a favourable pattern (i.e. major suppression of self-renewal versus terminal mitoses) following manipulation of culture conditions by the addition or removal of exogenous growth factors. In addition, in a further patient refractory to treatment with Decitabine in vivo, similar alterations of the culture conditions were unable to modify the unfavourable pattern of response to the drug in vitro. Our results indicate that the sensitivity of blast progenitors in suspension cultures strongly correlates with the remission outcome of the patients. From our data, it also appears that alterations of culture microenvironment are able to modify the response of AML blasts to Decitabine, unveiling the 'hidden' sensitivity of leukemic progenitors to the drug in cases characterized by a discrepancy between in vivo and in vitro results, i.e. apparent in vitro resistance and favourable clinical outcome.

Acute Disease↗
PubMed1992

Inhibition of the self-renewal capacity of blast progenitors from acute myeloblastic leukemia patients by site-selective 8-chloroadenosine 3',5'-cyclic monophosphate.

The physiologic balance between the two regulatory subunit isoforms, RI and RII, of cAMP-dependent protein kinase is disrupted in cancer cells; growth arrest and differentiation of malignant cells can be achieved when the normal ratio of these intracellular signal transducers of cAMP is restored by the use of site-selective cAMP analogs. In this study we evaluated the effects of the site-selective cAMP analog 8-chloroadenosine 3',5'-cyclic monophosphate (8-Cl-cAMP) on clonogenic growth of blast progenitors from 15 patients with acute myeloblastic leukemia and 3 patients affected by advanced myelodysplastic syndrome. Leukemic blast progenitors undergo terminal divisions, giving rise to colonies in methylcellulose. The self-renewal capacity of blast progenitors is conversely reflected in a secondary methylcellulose assay after exponential growth of clonogenic cells in suspension cultures. In all the samples tested, 8-Cl-cAMP, at micromolar concentrations (0.1-50 microM), suppressed in a dose-dependent manner both primary colony formation in methylcellulose and the recovery of clonogenic cells from suspension culture. Strikingly, in the samples from the entire group of patients, 8-Cl-cAMP was more effective in inhibiting the self-renewing clonogenic cells than the terminally dividing blast cells (P = 0.005). In addition, in four out of six cases studied, 8-Cl-cAMP was able to induce a morphologic and/or immunophenotypic maturation of leukemic blasts. An evident reduction of RI levels in fresh leukemic cells after exposure to 8-Cl-cAMP was also detected. Our results showing that 8-Cl-cAMP is a powerful inhibitor of clonogenic growth of leukemic blast progenitors by primarily suppressing their self-renewal capacity indicate that this site-selective cAMP analog represents a promising biological agent for acute myeloblastic leukemia therapy in humans.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Phorbol ester induced osteoclast-like differentiation of a novel human leukemic cell line (FLG 29.1).

Studies on human osteoclast formation have been hampered by lack of a defined isolated progenitor cell population. We describe here the establishment of a human leukemic cell line (designated FLG 29.1) from bone marrow of a patient with acute monoblastic leukemia. The cultured cells are predominantly undifferentiated leukemic blasts, but addition of 12-o-tetradecanoylphorbol 13-acetate (TPA; 0.1 microM) induces irreversible differentiation into adherent, non-dividing, multinucleated cells. TPA-treated cells bear surface antigens typical of fetal osteoclasts, degrade 45Ca-labeled devitalized bone particles, display tartrate-resistant acid phosphatase in both mononuclear and multinuclear cells and receptors for calcitonin. Calcitonin increases intracellular cAMP accumulation in TPA-treated cells. TPA-treated cells show some ultrastructural features of osteoclasts as evidenced by transmission EM. These results indicate that FLG 29.1 cells may represent an osteoclast committed cell population, which upon induction with TPA acquire some morphological, phenotypical, and functional features of differentiated osteoclasts.

Antigens, CD↗