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PubMed1993

Large-scale expansion of human stem and progenitor cells from bone marrow mononuclear cells in continuous perfusion cultures.

There is a growing consensus that clinical practice in the areas of bone marrow (BM) transplantation and gene therapy will rely on the ex vivo expansion of hematopoietic cells. We report here on the development of continuously perfused culture systems (bioreactor systems) that expand human stem and progenitor cells from BM mononuclear cell (MNC) populations obtained without cell enrichment. In three separate experiments, 10 bioreactors were each inoculated with 3 x 10(7) BM MNC from patients undergoing marrow harvest for autologous transplantation. At various times thereafter (between days 6 and 16), duplicate bioreactors were harvested and cells were analyzed. The bioreactors contained three cell populations that were analyzed separately: nonadherent cells; cells that were loosely adherent to the endogenously formed stromal layer; and an adherent cell layer that required trypsinization for removal. Total cell numbers increased continuously to give an overall 10-fold (range, 8- to 11-fold) expansion by day 14. The adherent stromal layer significantly expanded to more than 2 x 10(7) cells, but remained less than 6% of the total cell population. Colony-forming unit-granulocyte-macrophage (CFU-GM) numbers expanded 21-fold (range, 12- to 34-fold) by day 14 and, because this expansion was greater than that for total cells, CFU-GM were enriched by as much as fourfold by day 14. Burst-forming unit-erythroid (BFU-E) numbers peaked earlier than did CFU-GM numbers, with a 12-fold (range, 6- to 18-fold) expansion obtained on day 8. In contrast to CFU-GM, which were predominantly nonadherent, BFU-E were more evenly distributed between the three cell populations. Stem cell activity was measured by the long-term culture-initiating cell (LTC-IC) limiting dilution assay. The number of LTC-IC per reactor consistently increased with time in all cultures, resulting in a 7.5-fold (range, 3.4- to 9.8-fold) expansion. In summary, more than 3 billion cells, containing 12 million CFU-GM, were reproducibly generated from the equivalent of a 10 to 15 ml BM aspirate. These data indicate that small numbers of BM MNC can be readily expanded ex vivo in continuous perfusion cultures, and that such ex vivo expansion may have direct applications in clinical and experimental BM transplantation.

Bone Marrow Cells↗
PubMed1993

Effects of total-body irradiation on bone marrow erythroid burst-forming units (BFU-E) and hemopoietic regeneration in dogs.

The acute and long-term effects of total-body X irradiation (TBI) on early erythroid progenitors, burst-forming units (BFU-E), in the bone marrow of beagles were studied for midline tissue doses of 1.6 and 2.4 Gy. After both radiation doses the initial reduction in the concentration of BFU-E was greater than that found for the granulocyte-macrophage progenitor cells (GM-CFC) and thus was in general agreement with the higher in vitro radiosensitivity of BFU-E compared to GM-CFC. After TBI with 1.6 Gy the GM-CFC and BFU-E returned to their normal levels within 2-4 weeks without showing long-term radiation effects. In contrast, after TBI with 2.4 Gy the concentrations of GM-CFC and BFU-E remained below the pretreatment levels up to 1 year after exposure. For a given midline tissue dose, the extent of the long-term effect of radiation on the BFU-E in a certain bone marrow site seems to be dependent on the local radiation dose in the respective bone marrow space. The minor radiation effects observed in the erythrocyte concentration in the peripheral blood, the hematocrit, and the hemoglobin concentration point to the enormous compensatory capacity of the more mature erythropoietic transit population to increase the proliferative capacity upon demand.

Animals↗
PubMed1993

Erythroid potentiating activity of tissue inhibitor of metalloproteinases on the differentiation of erythropoietin-responsive mouse erythroleukemia cell line, ELM-I-1-3, is closely related to its cell growth potentiating activity.

The erythroid-potentiating activity (EPA) of the tissue inhibitor of metalloproteinase-1 (TIMP-1) was re-examined using ELM-I-1-3, a mouse erythroleukemia cell line, which responded well to erythropoietin. Depletion of pre-existing TIMP-1 from fetal calf serum in culture medium using monoclonal antibody suppressed erythropoietin-induced differentiation as measured by the induction of hemoglobin, commitment assay and globin mRNAs. The removal of TIMP-1 also suppressed the proliferation of ELM-I-1-3 as measured by cell number and de novo DNA synthesis. These changes were reversed by the addition of purified TIMP-1 to the culture medium. Anti-TIMP-1 antibody also blocked both hexamethylene bisacetamide (HMBA)-induced erythroid differentiation and the proliferation of both ELM-I-1-3 and Friend erythroleukemia cells. Considering previous reports analyzing the chemical induction of Friend mouse erythroleukemia cell differentiation, our results suggest that erythropoietin- or HMBA-induced erythroid differentiation might also be coupled with cell proliferation. Our 3H thymidine-uptake experiment shows that TIMP-1 removal was also effective in the inhibition of cell growth of various other cell lines in addition to erythroleukemia cell lines. These results suggest that EPA action of TIMP-1 on erythroid leukemia cell lines is closely related to its activity to promote the cell growth of various cell lines and cells including erythroleukemia cell lines.

Acetamides↗
PubMed1993

Insulin-like growth factors stimulate erythropoiesis in serum-substituted umbilical cord blood cultures.

The stimulatory effects of the insulin-like growth factors (IGFs) on erythroid colony formation by hematopoietic progenitor cells derived from adult bone marrow and peripheral blood have been well demonstrated. To enhance our understanding of the potential role of IGFs in human newborn erythropoiesis, we studied the effects of IGF-I and IGF-II on neonatal erythropoiesis in vitro. Erythroid progenitor cells were recovered from umbilical cord blood collected at scheduled Cesarean sections from women with term, uncomplicated pregnancies. Light-density cord blood mononuclear cells were cultured for 7 days in a serum-substituted culture system supplemented with and without purified human recombinant erythropoietin (0.5 to 2.0 U/mL) and recombinant human IGFs. Addition of IGF-I (1 to 100 ng/mL) resulted in up to a 4-fold increase over baseline erythropoietin-dependent colony formation at 7 days with a maximal effect at 10 ng/mL. While subphysiologic doses of IGF-II caused a modest stimulation of erythropoiesis, addition of a physiologic concentration (100 ng/mL) resulted in up to a 4-fold enhancement in erythroid colony formation. This stimulatory effect persisted in cultures of mononuclear cells that were depleted of monocytes, myeloid cells, T cells and B cells prior to culture, suggesting that enhancement is the result of a direct IGF effect on progenitor cells. Addition of IGFs in the absence of erythropoietin resulted in erythroid colony formation in some but not all experiments. Whereas IGF-I was the primary regulator of erythropoietin-independent erythroid colony formation by adult erythroid progenitors, IGF-II was the predominant regulator of erythropoietin-independent erythroid colony formation by neonatal progenitor cells. We conclude that IGFs in physiologic doses directly stimulate neonatal cord blood erythroid progenitor cells and may play a role in developmental control of human erythropoiesis.

Blood↗
PubMed1993

In vivo effects of recombinant interleukin-11 on myelopoiesis in mice.

Purified recombinant human interleukin-11 (rhuIL-11) was assessed for its in vivo effects on the proliferation and differentiation of hematopoietic progenitors as well as its capacity to accelerate the recovery of a drug-suppressed hematopoietic system. Dosage and time sequence studies demonstrated that administration of IL-11 to normal mice resulted in increases in absolute numbers of femoral marrow and splenic myeloid (granulocyte-macrophage colony-forming unit [CFU-GM], burst-forming unit-erythroid [BFU-E], CFU-granulocyte, erythroid, macrophage, megakaryocyte) progenitor cells and in stimulation of these progenitors to a higher cell cycling rate. This was associated with increased numbers of circulating neutrophils. Administration of IL-11 to mice pretreated with cyclophosphamide decreased the time required to regain normal levels of neutrophil and platelet counts in peripheral blood. In addition, IL-11 accelerated reconstitution to normal range of myeloid progenitors from bone marrow and spleen of myelosuppressed mice. These data suggest that IL-11 may play an important role in the regulation of hematopoiesis, and the application of this novel cytokine may have clinical therapeutic benefits.

Animals↗
PubMed1996

Inhibition of protein kinase C suppresses megakaryocytic differentiation and stimulates erythroid differentiation in HEL cells.

The bisindolylmaleimide, GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide ), a highly selective inhibitor of protein kinase C (PKC), was used to test the role of this enzyme in phorbol ester-induced megakaryocytic differentiation of HEL cells. Treatment of these cells with 10 nmol/L phorbol 12-myristate 13-acetate (PMA) for 3 days caused a complete inhibition of proliferation and a threefold increase in the surface expression of glycoprotein (GP) IIIa, a marker of megakaryocytic differentiation that forms part of the fibrinogen receptor complex, GPIIb/IIIa. A similar effect was observed with phorbol 12,13-dibutyrate, but not with the biologically inactive derivative PMA-4-O-methyl ether. The PMA-induced increase in GPIIIa expression was completely inhibited by GF109203X in a dose-dependent manner (IC50 = 0.5 mumol/L), with a maximal effect at 2.5 to 5.0 mumol/L. GF109203X also blocked the inhibitory effect of PMA on cell growth and inhibited PMA-stimulated phosphorylation of the 47-kD PKC substrate, pleckstrin. Incubation of HEL cells with 25 mumol/L hemin for 3 days caused a fourfold to fivefold increase in expression of the erythroid differentiation marker, glycophorin A. In contrast to the inhibitory effect of GF109203X on GPIIIa expression, hemin induction of glycophorin A was enhanced by this compound. Furthermore, GF109203X alone caused a dose-dependent increase in glycophorin A expression, and induced hemoglobinization. Consistent with these changes, Northern blot analysis revealed that GF109203X treatment reduced the steady-state level of GPIIb mRNA and increased those for glycophorin A and gamma-globin. These results suggest that PKC may act as a developmental switch controlling erythroid/megakaryocytic differentiation.

Aphidicolin↗
PubMed1996

Differential effects of nitric oxide on erythroid and myeloid colony growth from CD34+ human bone marrow cells.

Nitric oxide (NO) is a reactive molecule with numerous physiologic and pathophysiologic roles affecting the nervous, cardiovascular, and immune systems. In previous work, we have demonstrated that NO inhibits the growth and induces the monocytic differentiation of cells of the HL-60 cell line. We have also demonstrated that NO inhibits the growth of acute nonlymphocytic leukemia cells freshly isolated from untreated patients and increases monocytic differentiation antigens in some. In the present work, we studied the effect of NO on the growth and differentiation of normal human bone marrow cells in vitro. Mononuclear cells isolated from human bone marrow were cultured in semisolid media and treated with the NO-donating agents sodium nitroprusside (SNP) or S-nitroso-acetyl penicillamine (SNAP) (0.25 to 1 mmol/L). Both agents decreased colony-forming unit-erythroid (CFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) formation by 34% to 100%. When CD34+ cells were examined, we noted that these cells responded to SNP and SNAP differently than did the mononuclear cells. At a concentration range of 0.25 to 1 mmol/L, SNP inhibited the growth of CFU-E by 30% to 75%. However, at the same concentration range, SNP increased the number of CFU-GM by up to 94%. At concentrations of 0.25 to 1 mmol/L, SNAP inhibited the growth of CFU-E by 33% to 100%. At a concentration of 0.25 mmol/L, SNAP did not affect CFU-GM. At higher concentrations, SNAP inhibited the growth of CFU-GM. Although SNP increased intracellular levels of cGMP in bone marrow cells, increasing cGMP in cells by addition of 8-Br-cGMP (a membrane permeable cGMP analogue) did not reproduce the observed NO effects on bone marrow colonies. These results demonstrate that NO can influence the growth and differentiation of normal human bone marrow cells. NO (generated in the bone marrow microenvironment) may play an important role modulating the growth and differentiation of bone marrow cells in vivo.

Antigens, CD34↗
PubMed1996

Improvement of erythroid toxicity by lentinan and erythropoietin in mice treated with chemotherapeutic agents.

Lentinan, an antitumor polysaccharide, has been assessed for its potential in vivo to augment erythroid progenitor cells and protect them from the cytotoxic effects of antitumor chemotherapeutics. Lentinan augmented the level of burst-forming units-erythroid (BFU-E) and accelerated the recovery of the reduced number of BFU-E in mice treated with 5-fluorouracil (5-FU); lentinan did not influence red blood cell counts or colony-forming unit-erythroid (CFU-E) numbers in the femoral marrow. A significant decrease in stem cell inhibitory factor (SCIF) activities in bone marrow and an increase in colony-forming unit-spleen (CFU-S) formation were observed in the lentinan-treated mice. The mechanism of augmented BFU-E formation may be partly due to augmented production of stem cells, giving rise to both CFU-GM and BFU-E. Furthermore, when lentinan administration was followed by administration of erythropoietin (Epo) in 5-FU-treated mice, increases in femoral marrow and splenic CFU-E formation and augmentation of reticulocyte counts were observed beyond the level observed in mice treated with Epo alone. These results suggest that lentinan may augment the effects of Epo on erythropoiesis in the course of anemia and the decreased erythropoiesis in cancer patients receiving chemotherapy.

Animals↗
PubMed1996

Missense mutation of the erythropoietin receptor is a rare event in human erythroid malignancies.

Human erythroid malignancies (polycythemia vera [PV] and erythroleukemia) are associated with erythropoietin (Epo)-independent growth and differentiation. Missense or nonsense mutations in the Epo receptor (Epo-R) have been recently described in experimental erythroleukemia in mice and in cases of erythrocytosis in humans. To search for a similar genetic alteration in erythroleukemia and PV, we entirely sequenced the exons of the Epo-R gene as well as the intron-exon junctions in these disorders using polymerase chain reaction. In 1 of 10 cases of erythroleukemia, a single allele mutation was found in the 8th Epo-R gene exon that changed asparagine 487 into a serine. No Epo-r gene mutation was found in 12 PV cases studied, but the same mutation (N487S) was found in 1 patient with polycythemia that did not fulfill the criteria of PV (polycythemia of unknown origin). We did not detect this mutation after sequencing part of the 8th exon of the Epo-R gene from 21 other patients with polycythemia of unknown origin and 51 normal controls. The Epo-R mutation was also found in Epstein-Barr virus-derived cell lines from both cases, suggesting that it is not related to the malignant clone. Therefore, this mutation does not appear to be somatic, although no familial cases were found. The biologic effect of this mutation was subsequently studied. Erythroid progenitors from the polycythemic patient normally responded to Epo, whereas those from the erythroleukemic patient were Epo-independent due to autocrine stimulation by Epo. The normal and the mutated Epo-R were transfected into the murine Ba/F3 cell line. Both types of cells displayed the same response to Epo for proliferation, differentiation, and inhibition of apoptosis. Although this mutation may destroy a consensus binding site for Grb2, no obvious differences either in the pattern of Epo-induced tyrosine phosphorylated proteins or in the binding of Grb2 to the Epo-R were observed. In conclusion, a somatic Epo-R missense mutation does not appear to be a molecular mechanism involved in the abnormal growth of human erythroleukemia and PV. However, the Epo-R mutation (N487S) that we describe is located in the same tyrosine sequence beginning at AA 485 as the one previously observed (P488S) in as case of polycythemia (Sokol et al, Exp Hematol 22:447, 1994). These results suggest that this phosphopeptide sequence may play an important role in Epo signalling.

Base Sequence↗
PubMed1996

Large domains of apparent delayed replication timing associated with triplet repeat expansion at FRAXA and FRAXE.

Trinucleotide repeat expansions have been implicated in the causation of a number of neurodegenerative disorders. In the case of fragile X syndrome, full expansion of the FMR1 repeat element (CGG)n has also been correlated with replication timing delay of the locus and proximal flanking sequences in male lymphoblasts. To define more extensively this altered region of DNA replication, as well as to extend these studies to female cells containing premutant and mutant alleles, study of the replication timing properties of a >2-Mb zone in the FRAXA region (Xq27.3-q28) was undertaken by using a FISH technique. In this assay, relative times of replication of specific loci are inferred from the ratios of singlet and doublet hybridization signals in interphase nuclei. In all individuals with a full expansion of the trinucleotide repeat, a large (1-1.2-Mb) region of delayed timing was observed; the apparent timing of the earlier-replicating allele in female cells in this region was intermediate between normal and affected alleles in males, which is in accordance with expectations of a mixed population of cells resulting from random X inactivation. In addition, expansion of the nearby FRAXE locus also was found to correlate with replication timing delay, although the extent of the altered region was somewhat less. Trinucleotide repeat expansion thus may be acting in the Xq27.3-q28 region to alter long-range chromatin structure that could influence transcription of gene sequences within the affected domain.

Cells, Cultured↗
PubMed1996

Erythropoietin & erythroid progenitors in rats exposed to chronic hypoxia.

In order to better understand the mechanisms affecting erythropoietin (Epo) synthesis and red cell mass increase under chronic hypoxia, we examined Epo production and erythroid progenitors (CFU-E) in rats exposed to normobaric hypoxia for four weeks. Hypoxia induced the rise of hematocrit (Htc), hemoglobin (Hb) concentration and the red blood cell (RBC) number with a plateau in hematocrit values after two weeks. After 24 h of hypoxia, Epo levels were increased 20 fold, followed by a significant decrease. After the first week of hypoxia, the values were still higher than in the controls, but after two weeks Epo levels did not differ significantly from the normal values. The fall of Epo levels coincided with the plateau values of hematocrit. The changes in the CFU-E number followed the changes in Epo concentration: a two fold increase after 24 h of hypoxia; a further increase during the next two weeks reaching a peak on day 14, and then a progressive decrease at the time when Epo concentration was at a normal level. Although decreased, but still higher than normal, the CFU-E number during the last two weeks of hypoxia could be necessary for the maintenance of an achieved steady state under persistent hypoxic conditions with normal Epo concentration sufficient to maintain the existing rate of erythropoiesis.

Animals↗
PubMed1996

[The attachment of erythroid cells to solid supports in the presence of lectins].

A comparative influence of lectins on the attachment kinetics of erythroid cells (human erythrocytes and erythroleukemia cells K562) to glass formvar has been studied. It is shown that the inhibiting effect of wheat germ agglutinin (WGA) on the adhesion to glass is the same for both types of cells under study, whereas concanavalin A (Con-A) inhibits the erythrocyte adhesion to glass only but it is ineffective for adhesion of K562 cells. Plasmatic membranes of K562 cells are free from band 3 protein contrary to the erythrocyte ones. It is concluded that the inhibition of erythrocyte adhesion by lectins results from their binding to different components of cell membranes; sialic acid residues of glycophorin (WGA) or band 3 protein (Con-A). This conclusion is confirmed by the inhibiting effect of WGA towards attachment of cells K562 to glass and the absence of such an effect of Con-A towards the same cells which do not contain this protein. The most probable form of both cell type attachment to glass is the occurrence of so-called focal contacts. The latter can be easily observed in the case of K562 cells. The intact erythrocyte attachment to formvar occurs slower than to glass. At the same time, the above lectins accelerate the erythrocyte attachment to formvar.

Cell Adhesion↗
PubMed1998

Signaling through the interaction of membrane-restricted stem cell factor and c-kit receptor tyrosine kinase: genetic evidence for a differential role in erythropoiesis.

Mutations of the receptor tyrosine kinase c-kit or its ligand stem cell factor (SCF), which is encoded as a soluble and membrane-associated protein by the Steel gene in mice, lead to deficiencies of germ cells, melanocytes, and hematopoiesis, including the erythroid lineage. In the present study, we have used genetic methods to study the role of membrane or soluble presentation of SCF in hematopoiesis. Bone marrow-derived stromal cells expressing only a membrane-restricted (MR) isoform of SCF induced an elevated and sustained tyrosine phosphorylation of both c-kit and erythropoietin receptor (EPO-R) and significantly greater proliferation of an erythrocytic progenitor cell line compared with stromal cells expressing soluble SCF. Transgene expression of MR-SCF in Steel-dickie (Sld) mutants resulted in a significant improvement in the production of red blood cells, bone marrow hypoplasia, and runting. In contrast, overexpression of the full-length soluble form of SCF transgene had no effect on either red blood cell production or runting but corrected the myeloid progenitor cell deficiency seen in these mutants. These data provide the first evidence of differential functions of SCF isoforms in vivo and suggest an abnormal signaling mechanism as the cause of the severe anemia seen in mutants of the Sl gene.

Animals↗
PubMed1998

Distinct actions of Flt3 ligand and stem cell factor on myeloid lineage selection and maturation of granulocytes versus macrophages.

Flt3/Flk2 ligand (FL) and stem cell factor (SCF; c-kit ligand) interact with different but related surface receptor tyrosine kinases expressed on early hematopoietic cells. Both FL and SCF stimulate the proliferation of stem cells and progenitors, but the mechanisms by which these cytokines exert their functions are currently unknown. Here we show that FL and SCF have different effects on myeloid differentiation and lineage selection of early hematopoietic cells using a defined subpopulation of mouse bone marrow (BM) expressing c-Kit but lacking mature lineage markers (c-Kit+Lin-). SCF, together with IL-6, induced the differentiation of a large fraction of these progenitor cells toward mature granulocytes and to a lesser extent toward monocytes. In contrast, FL combined with IL-6 favored differentiation into mature monocytes and macrophages, and very few if any granulocytes could be identified. When FL and SCF were analyzed for their ability to support growth of multilineage erythroid colonies (pre-CFCmulti) and myeloid-committed colony-forming progenitors of granulocytes and monocytes (CFC-G/M), a clear discrepancy was also found. Both FL and SCF had synergistic effects on the proliferation of immature cells with blast-like morphology, but the expansion of pre-CFCmulti and CFC-G/M was favored by SCF but not by FL. FL synergized with both SCF and IL-6 with respect to proliferative response and maintenance of undifferentiated cells; however, the numbers of CFC-G/M after 7 or 14 days in culture were significantly lower than those observed with SCF combined with IL-6. Interestingly, in contrast to SCF, no pre-CFCmulti was recovered from BM cells expanded in the presence of FL and IL-6.

Animals↗
PubMed1998

An improved serum free system for cloning human "pure" erythroid colonies. The role of different growth factors and cytokines on BFU-E formation by the bone marrow and cord blood CD34+ cells.

We have developed an efficient serum free culture model for cloning human erythroid progenitors. Accordingly, human bone marrow or cord blood CD34+ cells if plated in our serum free medium and stimulated with a mixture of EpO + KL, grow erythroid colonies exclusively. Cells isolated from these cultures express glycophorin-A (GPA-A), are CD33-, IIb/IIIa-, and finally all become hemoglobinized. By employing this system we also found out that cord blood CD34+ mononuclear cells (MNC) contain more BFU-E than adult marrow CD34+ MNC, moreover, the erythroid colonies formed by cord blood progenitors are significantly larger then the ones formed by the marrow cells. We have also compared the influence of different cytokines and growth factors, which were reported in the literature to costimulate BFU-E growth on cloning efficiency of human BFU-E cultured in our serum free medium. We found that from 20 different growth factors and cytokines tested, EpO dependent bone marrow BFU-E growth is costimulated only by KL, and to lesser degree also by IL-3, GM-CSF, TpO and IL-9. In contrast to marrow cells we observed that cord blood BFU-E in addition to KL, IL-3, GM-CSF, TpO, LIF and IL-9 were also costimulated by NGF-beta, FGF-1, FGF-2 and STK-IL. We found simultaneously that TPO which possess only negligible costimulatory effect on erythroid colony formation by bone marrow CD34+ cells, significantly costimulated the formation of erythroid colonies grown by cord blood CD34+ cells. Therefore, the cord blood CD34+ cells are largely committed to erythroid differentiation, and, moreover, they respond to a wider spectrum of the growth factors than their bone marrow counterparts.

Antigens, CD34↗
PubMed1998

The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit.

We recently showed that a retrovirally transduced prolactin receptor (PrlR) efficiently supports the differentiation of wild-type burst-forming unit erythroid (BFU-e) and colony-forming unit erythroid (CFU-e) progenitors in response to prolactin and in the absence of erythropoietin (Epo). To examine directly whether the Epo receptor (EpoR) expressed by wild-type erythroid progenitors was essential for their terminal differentiation, we infected EpoR-/- progenitors with retroviral constructs encoding either the PrlR or a chimeric receptor containing the extracellular domain of the PrlR and intracellular domain of EpoR. In response to prolactin, both receptors were equally efficient in supporting full differentiation of the EpoR-/- progenitors into erythroid colonies in vitro. Therefore, there is no requirement for an EpoR-unique signal in erythroid differentiation; EpoR signaling has no instructive role in red blood cell differentiation. A synergistic interaction between EpoR and c-kit is essential for the production of normal numbers of red blood cells, as demonstrated by the severe anemia of mice mutant for either c-kit or its ligand, stem cell factor. We show that the addition of stem cell factor potentiates the ability of the PrlR to support differentiation of both EpoR-/- and wild-type CFU-e progenitors. This synergism is quantitatively equivalent to that observed between c-kit and EpoR. Therefore, there is no requirement for an EpoR-unique signal in the synergistic interaction between c-kit and EpoR.

Animals↗
PubMed1998

Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production.

A defect in erythropoietin (EPO) production has been advocated as being the main cause of anemia presented at time of diagnosis or during treatment by adults with solid tumors. On the basis of this defect, anemic cancer patients, both adults and children, have been treated with recombinant human EPO (rHuEPO). To further elucidate the pathophysiology of anemia in children with cancer, we measured serum soluble transferrin receptor (sTfR), a quantitative marker of erythropoiesis, and serum EPO at time of diagnosis and during chemotherapy in children suffering from solid tumor or leukemia. We determined serum EPO in 111 children (55 leukemia, 56 solid tumors) at time of diagnosis. In the last 44 patients (23 leukemia and 21 solid tumors), sTfR levels were also measured. Serum EPO together with sTfR levels were also determined in 60 children receiving chemotherapy (29 leukemia, 31 solid tumors). These results were compared with those obtained from appropriate control groups. In all patients, we found a highly significant correlation between the logarithm of EPO (log[EPO]) and the hemoglobin (Hb) level. In all subsets of patients, sTfR levels were inappropriately low for the degree of anemia. Neither leukemic nor solid tumor groups showed a significant inverse relationship between log(sTfR) and the Hb level as would be expected in anemic patients with appropriate marrow response. Thus, in children with cancer, anemia is associated with a decreased total bone marrow erythropoietic activity which, in contrast to what has been reported in anemic cancer adults, is not related to defective EPO production.

Adolescent↗