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B Nakamoto

Publications and source records attributed to B Nakamoto.

At least 19 recordsLinked to original sources
PubMed1998

Anti-VLA4/VCAM-1-induced mobilization requires cooperative signaling through the kit/mkit ligand pathway.

Although a large body of data on mobilization have yielded valuable clues, the mechanism(s) dictating egress of stem/progenitor cells during baseline hematopoiesis and after their mobilization are poorly understood. We have previously provided functional in vivo evidence that cytoadhesion molecules, specifically the beta1 integrins, are involved in mobilization; however, the mechanism by which this was achieved was unclear. To provide further insights into the anti-very late antigen 4 (VLA4)/anti-vascular cell adhesion molecule 1 (VCAM-1)-induced mobilization, we used these antibodies to treat mutant mice with compromised growth factor receptor function. We found that mobilization by anti-VLA4 does not depend on a functional granulocyte colony-stimulating factor, interleukin-7 (IL-7), or IL-3alpha receptor. By contrast, the functional kit receptor is required, because W/Wv mice responded minimally, whereas Steel-Dickie (Sl/Sld) responded normally. Both Wv and Sl/Sld mice did not respond to anti-VCAM-1 treatment, in contrast to their +/+ littermates and despite normal levels of VCAM-1 expression in bone marrow cells. The defective response to anti-VCAM-1 in W/Wv mice was corrected after their transplantation with +/+ cells. mev/mev mice showed increased numbers of circulating progenitors before treatment and a heightened response after anti-VLA4 or anti-VCAM-1 treatment. Downmodulation of kit expression was detected in normal bone marrow cells after anti-VLA4 treatment. On the strength of the above findings we conclude that (1) anti-VLA4/VCAM-1-induced mobilization likely requires signaling for stimulation of cell migration; (2) this cooperative signaling involves the kit/kit ligand pathway, and provides a novel example of integrin/cytokine crosstalk; and (3) migration mediated through the kit/kit ligand pathway may be a common contributor to different mobilization stimuli. Dissection of the exact molecular pathways that lead to mobilization remains a future challenge.

Animals↗
PubMed1997

Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice.

Although the use of cytokine-mobilized peripheral blood stem cells has gained a significant momentum in clinical transplantation, the mobilization schemes practiced are guided by a great deal of empiricism. The mechanism(s) by which cytokines or chemokines, alone or in combination, bring about redistribution of stem/progenitor cells from bone marrow to peripheral blood are poorly understood. Likewise the fate of mobilized stem/progenitor cells and their biological properties are incompletely defined. One of the leading hypotheses to explain the mechanism of cytokine-induced mobilization encompasses the view that cytokines disrupt, directly or indirectly, cytoadhesive interactions of stem/progenitor cells with their bone marrow stroma. Compatible with this view are changes in the expression and/or function of several cytoadhesion molecules, especially integrins, postmobilization, and extensive in vitro experimentation supporting the concept of cytokine/integrin interactions. To provide a further insight on the cytokine/integrin interplay in vivo, we have combined cytokine treatments with anti-integrin treatments for mobilization in primates and mice. We found that anti-VLA4 treatment combined with either granulocyte colony-stimulating factor (G-CSF ) treatment or kit ligand treatment leads to significant enhancement of mobilization efficiency (fivefold to eightfold) well above the levels produced by either cytokine alone or anti-VLA4 treatment alone. Similar enhancement was seen when combinations of cytokines, ie, G-CSF plus kit ligand or G-CSF plus Flt3-ligand were used with anti-VLA4 in primates and mice. Furthermore, when anti-VLA4 was given in 5-Fluorouracil-treated primates, significant numbers of progenitor cells were circulating for several days during the recovery period only in the anti-VLA4 treated animals. These data suggest that (1) the effect of anti-VLA4 on mobilization, when used alone, is unlikely to be mediated by secondary cytokine elaboration in vivo; (2) three different cytokines and their combinations do not appear to influence the in vivo responsiveness to anti-VLA4 in coadministration schemes; (3) even if cytokine treatments on their own exert downmodulation of VLA4 function, the target progenitor cells influenced by anti-VLA4 or by cytokines may not necessarily overlap; and (4) augmentation of mobilization in cytokine/anti-VLA4 treatments is most likely caused by an amplification of the pool of target cells on which anti-VLA4 exerts its effects. Because cytokines or anti-VLA4 are each capable of mobilizing long-term repopulating cells and because we show with the present studies that anti-VLA4 in an autologous bone marrow cell transplantation setting does not cause any delay in engraftment, the combination of cytokine/anti-integrin treatment enhancing mobilization may have a clinical use.

Animals↗
PubMed1997

In vivo effects of Flt3/Flk2 ligand on mobilization of hematopoietic progenitors in primates and potent synergistic enhancement with granulocyte colony-stimulating factor.

The Flt3 receptor is expressed in primitive hematopoietic cells and its ligand exerts proliferative effects on these cells in vitro in synergy with other cytokines. To expand on the functional properties of Flt3 ligand (FL) in vivo we treated nonhuman primates with FL and tested its ability to mobilize stem/progenitor cells when given alone or in combination with granulocyte colony-stimulating factor (G-CSF) treatment. FL alone (200 microg/kg/day) mobilizes progenitors with slow kinetics and with a peak effect at the end of 2 weeks of treatment. The spectrum of mobilized progenitors includes myeloid, lymphoid, megakaryocytic, and osteoclastogenic but a low proportion of burst-forming unit (BFU)e. Bone marrow (BM) studies before and during the treatment suggested that proliferative effects in BM may have preceded effects on peripheral blood mobilization. To assess the synergy of FL with G-CSF in mobilization of progenitors we used two schemes: one in which G-CSF was used for the last 5 days of a 12-day treatment with FL; the other in which both cytokines were given concurrently for 5 days only (FL, 200 microg/kg; G-CSF, 100 microg/kg). Both schemes yielded much higher progenitor mobilization levels (peak levels of colony-forming cells [CFSs] 41,000 to 95,000/mL blood) than observed with either FL (CFC 4,600 to 7,300/mL) or G-CSF (8,405 +/- 3,024/ mL) used alone at the same doses. Furthermore, there was a progressive and significant expansion of progenitors in vitro during 2 weeks in suspension cultures of mononuclear cells or of CD34+ cells only in the animal with the combined treatment. Likewise, substantial mobilization of osteoclastogenic progenitors was documented only with the combined treatment. Given the functional properties of FL, its synergistic mobilization with G-CSF, and its anticipated good tolerance (because of the absence of an effect on mast cell activation), a clinical use is projected for this cytokine in peripheral blood transplantation settings, as well as in experiments with ex vivo gene transfer.

Animals↗
PubMed1997

The role of CS1 moiety of fibronectin in VLA mediated haemopoietic progenitor trafficking.

In vitro the integrin VLA4 mediates the adhesion of haemopoietic progenitors to bone marrow stroma through an interaction with its ligands VCAM-1 and the CS1 moiety of fibronectin. The VLA4/VCAM-1 pathway has been implicated in haemopoietic trafficking in vivo since antibodies to both VLA4 and VCAM-1 decrease the homing (lodgement) of transplanted progenitors and mobilize progenitors. However, the role of the CS1 domain of fibronectin in progenitor trafficking in vivo has not been explored. We studied the effect of competitive inhibition of the VLA4/CS1 pathway on progenitor homing and mobilization in mice. Pre-incubation of bone marrow cells with a CS1 inhibitor did not alter the number of CFU-C or CFU-S12 lodged to the bone marrow of lethally irradiated mice 3 h after transplantation. In addition, continuous administration of a CS1 inhibitor did not increase the number of CFU-C in the peripheral blood. In order to study the role of the VLA4/CS1 pathway in trafficking of more primitive progenitors we studied whether administration of a CS1 inhibitor mobilized radioprotective cells. In contrast to the effect of anti-VCAM-1 which mobilized cells capable of rescuing 100% of lethally irradiated mice, administration of a CS1 inhibitor did not increase the number of radioprotective cells in the peripheral blood. Haemopoietic progenitors also bind to the RGD motif of fibronectin through an interaction with VLA5 and we therefore also studied the effect of antibodies to VLA5 on progenitor homing and mobilization. Antibody to VLA5 did not alter bone marrow lodgement at 3 h or increase the number of circulating haemopoietic progenitors. These studies therefore imply that, in contrast to VCAM-1, the CS1 moiety of fibronectin is not a significant ligand in VLA4 mediated progenitor trafficking in vivo.

Animals↗
PubMed1996

Identification of new genes expressed in a human erythroleukemia cell line.

We cloned novel cDNAs from MB02 human erythroleukemia cells using PCR based approaches: a) Differential display by means of RT-PCR using one 5' primer CTTGATTGCC and four different 3' primers (T12AA, T12CA, T12GA, and T12AT). Ninety-three percent of the differential clones which were reamplified and sequenced were cDNAs of previously unidentified genes. b) Cloning using degenerate TFIIIA-like zinc finger domain specific oligonucleotide. Of the 54 clones sequenced, 20 contained two or more zinc finger sequences. Ten of these clones were new zinc finger cDNAs and one belonged to a known zinc finger gene (ZFP7). c) Cloning using degenerate tyrosine kinase(TK) domain-specific oligonucleotides corresponding to the highly conserved amino acid sequences IHRDLAA and DVWSFG. Of the 28 cDNA clones sequenced, 7 were JAK1 TK, one was atk TK, one was tec TK. The remaining sequences belonged to new ESTs or to ribosomal genes. d) Cloning using degenerate POU domain-specific oligonucleotides corresponding to sequence FK(QV)RRIK of the POU-specific domain and to sequence VWFCN(RQ)R of the POU-homeodomain. Sixteen clones were sequenced and all but one were identical with the Oct-1 transcriptional factor. Differential display RT-PCR and PCR-based cDNA cloning using degenerate primers for zinc finger motifs yielded the largest number of new genes expressed in MBO2 cells.

Amino Acid Sequence↗
PubMed1995

The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen.

Selective lodgement or homing of transplanted hemopoietic stem cells in the recipient's bone marrow (BM) is a critical step in the establishment of long-term hemopoiesis after BM transplantation. However, despite its biologic and clinical significance, little is understood about the process of homing. In the present study, we have concentrated on the initial stages of homing and explored the functional role in vivo of some of the adhesion pathways previously found to mediate in vitro adhesion of hemopoietic cells to cultured BM stroma. We have found that homing of murine hemopoietic progenitors of the BM of lethally irradiated recipients at 3 h after transplant was significantly reduced after pretreatment of the donor cells with an antibody to the integrin very late antigen 4 (VLA4). This inhibition of marrow homing was accompanied by an increase in hemopoietic progenitors circulating in the blood and an increased uptake of these progenitors by the spleen. Similar results were obtained by treatment of the recipients with an antibody to vascular cell adhesion molecule 1 (VCAM-1), a ligand for VLA4. Furthermore, we showed that administration of the same antibodies (anti-VLA4 or anti-VCAM-1) to normal animals causes mobilization of hemopoietic progenitors into blood. These data suggest that hemopoietic cell lodgement in the BM is a regulatable process and can be influenced by VLA4/VCAM-1 adhesion pathway. Although additional molecular pathways are not excluded and may be likely, our data establish VCAM-1 as a BM endothelial addressin, analogous to the role that mucosal addressin cell adhesion molecule (MAdCAM) plays in lymphocyte homing. Whether splenic uptake of hemopoietic progenitors is passive or controlled through different mechanisms remains to be clarified. In addition, we provide experimental evidence that homing and mobilization are related phenomena involving, at least partly, similar molecular pathways.

Animals↗
PubMed1994

Fetal hemoglobin induction by acetate, a product of butyrate catabolism.

Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in gamma-globin protein and gamma mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of gamma/gamma + beta mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in gamma-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of gamma-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb mu locus control region (mu LCR) cassette linked to a 3.3-kb A gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of gamma-globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

Acetates↗
PubMed1993

Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin.

Interaction of hemopoietic cells with the elements of the underlying bone marrow stroma, the unique site of their "homing" in adult individuals, is essential for sustained normal hemopoiesis. However, the specific molecules responsible for homing and for the continuing interaction of hemopoietic cells with the bone marrow stromal cells in vivo, or those involved in progenitor/stem cell trafficking through the bloodstream, have not been defined. A large repertoire of adhesion receptors, especially of the integrin family, appear to play a prominent role in promoting adhesion of hemopoietic stem cells to cultured marrow stromal cells in vitro. To test the functional role of cytoadhesion molecules in vivo, we treated primates systemically with either anti-alpha 4- or anti-beta 2-integrin antibodies, whose antigens are found in the majority of hemopoietic progenitors and in many differentiated cells. We found that anti-alpha 4 (anti-VLA4, anti-CD49d) but not anti-beta 2 (anti-CD18) treatment selectively mobilized progenitors into the bloodstream (up to 200-fold). Peripheralization involved erythroid, myeloid, and mixed progenitors; was detectable 24 hr after a single anti-VLA4 injection; and lasted beyond the days of treatment. Anti-VLA4 treatment additively augmented peripheralization of progenitors in animals with a preceding course of granulocyte-colony-stimulating factor. These data provide insight on the involvement of VLA4 antigens in the in vivo trafficking of progenitors and are of relevance to collection of peripheral blood stem cells for transplantation.

Animals↗
PubMed1991

Diamond-blackfan anemia: in vitro response of erythroid progenitors to the ligand for c-kit.

To provide insights into the pathogenesis of Diamond-Blackfan anemia, we examined the in vitro response of erythroid progenitors to the recently isolated ligand for c-kit (stem cell factor, SCF). For these studies, marrow or blood mononuclear cells from 10 Diamond-Blackfan patients were cultured with erythropoietin (Ep), Ep and interleukin-3, Ep and granulocyte-macrophage colony-stimulating factor, or Ep and lymphocyte conditioned media (LCM). These combinations were tested in the presence or absence of SCF. The mean number of cells per erythroid burst increased 5 to 50-fold in cultures containing SCF. Furthermore, many additional erythroid bursts were seen (mean increment 3.2 x baseline values). Although burst-forming unit-erythroid (BFU-E) from all patients responded, there were differences among individuals in the sensitivity of their BFU-E to SCF. In six patients and all control studies, plateau frequencies of erythroid bursts were achieved with less than or equal to 10 ng/mL SCF, whereas in studies from the other four patients, over 50 ng/mL SCF was required. These data invite speculation that the c-kit receptor/ligand axis is involved in the pathogenesis of Diamond-Blackfan anemia. More importantly and regardless of whether the observed patterns of response reflect the primary defect or an epiphenomenon, our data strongly support a therapeutic trial of SCF in patients with Diamond-Blackfan anemia.

Adolescent↗
PubMed1991

Erythropoietin receptor characteristics on primary human erythroid cells.

Erythropoietin (EP) exerts its effects on erythropoiesis by binding to a cell surface receptor. We examined EP receptor expression during normal human erythroid differentiation and maturation from the burst-forming unit-erythroid (BFU-E) to the reticulocyte level. In contrast to previous studies, we assessed EP receptor number and affinity in erythroid precursors immunologically purified from fresh bone marrow aspirates or fetal liver samples and in reticulocytes purified from peripheral blood. EP receptors were quantitated by equilibrium binding experiments with 125I EP. We found that purified primary erythroblasts from both adult and fetal sources exhibited a single high-affinity (kd 100 pmol/L) binding site for EP under our experimental conditions, and 135 or 250 receptors per cell, respectively. Reticulocytes were devoid of EP receptors. We compared these data to in vitro-derived BFU-E progeny at both early and late stages of maturation. Cultured BFU-E progeny also displayed a single class of receptors of slightly lower affinity (210 to 220 pmol/L). Preparations enriched in colony-forming units-erythroid (CFU-E) and proerythroblasts (day 9 BFU-E progeny) displayed approximately 1,100 receptors per cell, whereas populations containing mature erythroblasts (day 14 BFU-E progeny) exhibited approximately 300 receptors per cell. Furthermore, information from binding experiments was complemented by autoradiography in both enriched BFU-E preparations, cultured BFU-E progeny (days 9 and 14), and marrow mononuclear cells. These studies are consistent with a peak in EP receptor expression at the CFU-E/proerythroblast stage and a decrease with further maturation to undetectable levels at the reticulocyte stage. These data examining EP receptor characteristics on freshly isolated erythroid precursor cells complement previous data on EP receptor biology using culture-derived erythroblasts.

Autoradiography↗
PubMed1991

Expression of embryonic globins by erythroid cells in juvenile chronic myelocytic leukemia.

Juvenile chronic myelocytic leukemia (JCML) is a rare hematopoietic neoplasia of early childhood with distinct hematologic and biochemical features. We studied the biologic properties and the globin synthetic profiles of JCML erythroid cells both in vivo and in vitro from a total of 24 patients. In these cases we observed the exuberant colony-forming unit-macrophage (CFU-M) colony growth, as reported previously. Furthermore, in contrast to previous reports, we found significant erythroid colony growth in most of our cases (average: 1,182 burst-forming unit-erythroid [BFUe] per 10(5) plated cells, range: 40 to 6,927). This growth was by and large erythropoietin-dependent and was not greatly influenced by other added cytokines. By several criteria all erythroid colony growth detected in vitro was derived from JCML progenitors. The globin synthetic profile of JCML erythroid cells showed high levels of fetal hemoglobin both in vivo and in vitro (gamma/gamma + beta: 53% to 94% in reticulocytes, 62% to 98% in BFUe-derived cells). In addition (in seven cases studied) we detected embryonic globins (epsilon and zeta) at the protein and messenger RNA level, a novel finding for primary leukemic cells. We speculate that the transformed erythroid cells in JCML harbor a trans environment supporting expression of developmentally earlier genes (fetal, embryonic). However, in contrast to other acute or subacute leukemias, JCML erythroid cells also have the ability to reach full maturation to the red cell level, thus allowing detection of this primitive program in vivo.

Bone Marrow↗
PubMed1990

Autonomous developmental control of human embryonic globin gene switching in transgenic mice.

The mechanisms by which expression of the beta-like globin genes are developmentally regulated are under intense investigation. The temporal control of human embryonic (epsilon) globin expression was analyzed. A 3.7-kilobase (kb) fragment that contained the entire human epsilon-globin gene was linked to a 2.5-kb cassette of the locus control region (LCR), and the developmental time of expression of this construct was studied in transgenic mice. The human epsilon-globin transgene was expressed in yolk sac-derived primitive erythroid cells, but not in fetal liver or bone marrow-derived definitive erythroid cells. The absence of epsilon gene expression in definitive erythroid cells suggests that the developmental regulation of the epsilon-globin gene depends only on the presence of the LCR and the epsilon-globin gene itself (that is, an autonomous negative control mechanism). The autonomy of epsilon-globin gene developmental control distinguishes it from the competitive mechanism of regulation of gamma and beta-globin genes, and therefore, suggests that at least two distinct mechanisms function in human hemoglobin switching.

Animals↗
PubMed1990

Fetal calf serum contains activities that induce fetal hemoglobin in adult erythroid cell cultures.

Cultures of peripheral blood or bone marrow erythroid progenitors display stimulated production of fetal hemoglobin. We investigated whether this stimulation is due to factors contained in the sera of the culture medium. Comparisons of gamma/gamma + beta biosynthetic ratios in erythroid colonies grown in fetal calf serum (FCS) or in charcoal treated FCS (C-FCS) showed that FCS-grown cells had significantly higher gamma/gamma + beta ratios. This increase in globin chain biosynthesis was reflected by an increase in relative amounts of steady-state gamma-globin mRNA. In contrast to its effect on adult cells, FCS failed to influence gamma-chain synthesis in fetal burst forming units-erythroid (BFU-E) colonies. There was a high correlation of gamma-globin expression in paired cultures done with C-FCS or fetal sheep serum. Dose-response experiments showed that the induction of gamma-globin expression is dependent on the concentration of FCS. These results indicate that FCS contains an activity that induces gamma-globin expression in adult erythroid progenitor cell cultures.

Adult↗
PubMed1990

Dynamics of erythropoietin receptor expression on erythropoietin-responsive murine cell lines.

We examined erythropoietin receptor expression in two murine cell lines, B6SUtA and DA-1, that respond to erythropoietin in different ways. While B6SUtA cells undergo erythroid differentiation with limited proliferation after addition of erythropoietin, DA-1 cells show only a proliferative response. Equilibrium binding experiments with 125I-erythropoietin revealed that both B6SUtA and DA-1 cells express a single class of erythropoietin receptors. In the absence of erythropoietin, B6SUtA cells exhibited 145 receptors per cell with a dissociation constant (kd) of 380 pmol/L. Six days after induction with erythropoietin, the B6SUtA cells displayed 310 receptors per cell without a change in binding affinity; exposure to erythropoietin also increased cellular hemoglobin content. DA-1 cells adapted to erythropoietin-dependent growth over a period of months and exhibited a progressive increase in erythropoietin receptor expression, from 85 per cell (kd = 540) to 550 per cell (kd = 530), although the cells remained uniformly benzidine-negative. We interpret the data with B6SUtA cells to indicate that early erythroid differentiation stages are attended by an increase in erythropoietin receptor display, coordinate with the initiation of expression of erythroid-specific genes. In contrast, the results with DA-1 cells are most compatible with clonal selection as the mechanism underlying enhanced receptor expression. Thus, display of the erythropoietin receptor is dynamic and can be modulated during the course of erythropoietin-induced differentiation.

Cell Differentiation↗
PubMed1988

Erythropoietin changes the globin program of an interleukin 3-dependent multipotential cell line.

B6SUtA is a factor-dependent murine cell line of adult origin displaying the functional properties of a multipotent hematopoietic stem cell. We analyzed the globin programs of B6SUtA cells undergoing erythroid differentiation in both suspension and clonal cultures. In the absence of added erythropoietin, a small number of hemoglobinized cells were present, and these expressed predominantly embryonic globin. Addition of erythropoietin increased the number and maturation of hemoglobinized cells and led to a preferential augmentation of adult globin. Analysis of individual B6SUtA erythroid bursts showed that embryonic and adult globin can be expressed in cells derived from a single progenitor. Furthermore, by studying globin expression in cultured cells from mouse embryos, we found that the globin programs of B6SUtA cells are similar to those of erythroid progenitors at the period of transition from yolk sac to fetal liver erythropoiesis. Since B6SUtA cells are derived from adult bone marrow and they have the capacity to express embryonic globin, we speculate that the globin locus is not irreversibly modified during development and that adult cells at early stages of erythroid differentiation can transiently express ontogenetically primitive globin programs.

Animals↗
PubMed1988

Surface antigenic profile and globin phenotype of two new human erythroleukemia lines: characterization and interpretations.

Detailed characterization of the composite phenotype of two newly established erythroleukemia lines (OCIM1, OCIM2) shows that these lines share many of their erythroid markers (ie, surface antigens and globin program) as well as several of their nonerythroid properties (myeloid/monocytic/megakaryocytic) with the two known erythroleukemia lines (K562, HEL). In addition, each displays novel and instructive features. We argue that the surface and globin phenotype of all erythroleukemia lines is nonrandom and that it may be of physiologic relevance; it could represent the most prevalent phenotype of cells transformed by leukemia in vivo, and it raises the possibility that cells with similar potentials exist transiently during normal hematopoietic differentiation before their irreversible commitment to a single lineage. As such, these cells demonstrate a greater phenotypic adaptability in vitro than do their single lineage-committed counterparts since they can differentiate toward more than one lineage.

Antigens, Surface↗
PubMed1987

Constitutive and inducible secretion of platelet-derived growth factor analogs by human leukemic cell lines coexpressing erythroid and megakaryocytic markers.

We have examined the constitutive and inducible secretion of platelet-derived growth factor (PDGF)-like proteins in a variety of human hemopoietic cell lines. The highest levels of secreted protein were noted in four human erythroleukemia lines which, in addition to erythroid lineage markers, express one or more megakaryocytic lineage markers. Induction of these lines by 12-O-tetradecanoylphorbol-13-acetate enhanced the expression of megakaryocytic markers and increased secretion of PDGF-like proteins several fold. In concert with these changes, there was significant induction of c-sis/PDGF-B messenger RNA (mRNA) expression in all lines, whereas one line showed significant concurrent induction of PDGF-A mRNA expression. Whether PDGF-like secretion is part of the stem cell-like phenotype displayed by these lines or is secondary to their leukemic transformation remains to be determined. Nevertheless, these lines provide new cellular models for studying the expression and function of PDGF analogs in hemopoietic cells.

Cell Differentiation↗