Abstract
Sickle cell anemia (SS) patients can be divided into two sub-populations according to peripheral HbF levels. Patients with low (<9%) HbF levels (LFSS) are characterized by an increased number of circulating BFU-E in active DNA synthesis, and release of burst promoting activity (BPA) by unstimulated low density (LD) adherent cells. In contrast, circulating BFU-E from SS patients with high (>9%) HbF levels (HFSS) are normal in number, largely in resting phase, and their LD cells do not release BPA-like activity.
More recently further heterogeneity has been found among these two groups. In LFSS patients GM-CSF is constitutively produced by unstimulated monocytes. In contrast, HFSS patients' adherent cell depletion increases cycling of BFU-E in culture. CM from HFSS patients inhibits BFU-E expression in culture. Hence, LD adherent cells from HFSS patients may release an inhibitory factor(s). The nature of this factor has to be determined.
In addition, there are distinct subpopulations of BFU-E responsiveness to growth factor (GM-CSF, IL-3): a) LFSS patients have a homogeneous BFU-E population, equally responsive to GM-CSF and IL-3; b) HFSS patients, in addition to this subpopulation, have a subset of BFU-E dependent exclusively on IL-3 which is 20 to 40% of the total number of circulating BFU-E. This is similar to BFU-E from normal individuals. Hence, LFSS BFU-E represent an actively proliferating population, equally responsive to GM-CSF and IL-3, controlled by at least constitutively produced GM-CSF and possibly other factors.
These observations suggest a significant modification in BFU-E behavior in the subset of SS patients with low HbF levels and high hemopoietic stress. The heterogenous regulation of BFU-E in SS disease seems to be an epiphenomenon of HbF levels, and not vice-versa.
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Literature
Axelrad, A. A., Some hemopoietic negative regulators. Exp. Hemat.18 (1990) 143–150.
Bagby, G. C., Dinarello, C. A., Wallace, P., Wagner, C., Hefeneider, S., and McCall, F., Interleukin-1 stimulates granulocyte macrophage colony stimulating activity release by endothelial cells. J. clin. Invest.78 (1986) 1316–1323.
Bhaumik, K., Variations in growth responsiveness of burst forming units—erythroid colonies. Blood75 (1990) 524.
Cameron, P. M., Limjuce, G. A., Chin, J., Silberstein, L., and Schmidt, J. A., Purification to homogeneity and amino acid sequence analysis of two anionic species of human interleukin-1. J. exp. Med.164 (1986) 237–250.
Chervenick, P. A., and LoBuglio, A. F., Human blood monocytes: Stimulators of granulocyte and mononuclear colony formation in vitro. Science178 (1972) 164–166.
Clark, S. C., and Karmen, R., The human hematopoietic colony-stimulating factors. Science236 (1987) 1229–1236.
Croizat, H., Billett, H. H., and Nagel, R. L., Heterogeneity in the properties of burst-forming units of erythroid lineage in sickle cell anemia: DNA synthesis and burst-promoting activity production is related to peripheral hemoglobin F levels. Blood75 (1990) 1006–1010.
Croizat, H., and Nagel, R. L., Increased BPA production modulates EpO sensitivity of circulating BFU-E in sickle cell anemia. Blood70 (1987) 1319a.
Croizat, H., and Nagel, R. L., DNA synthesis of 14-day circulating erythroid progenitor cells in inversely correlated with HbF levels of sickle cell anemia patients. Blood72 (1988) 243a.
Croizat, H., and Nagel, R. L., Circulating BFU-E in sickle cell anemia: Relationship to percent fetal hemoglobin and BPA-like activity. Exp. Hemat.16 (1988) 946–949.
Croizat, H., and Nagel, R. L., DNA synthesis of 14-day erythroid progenitor cells and BPA production are inversely correlated with HbF levels of sickle cell anemia patients, in: Proc. 4th Ann. Symp. Molec. Biol. Erythropoiesis, 1988.
Croizat, H., and Nagel, R. L., Increased BPA production modulates EpO sensitivity of circulating BFU-E in sickle cell anemia, in: Proc. 3rd Ann. Symp. Molec. Biol. Hemopoiesis, pp. 311–317. Eds M. Tavassoli, E. D. Zanjani, J. L. Ascensao, N. G. Abraham and A. S. Levine. Plenum Publishing Co., New York 1988.
Croizat, H., and Nagel, R. L., GM-CSF is a component of the BPA like activity expressed by circulating low density mononuclear cells in sickle cell anemia. Blood74 (1989) 1191a.
Croizat, H., and Nagel, R. L., Identification of hemopoietin present in media conditioned by LD mononuclear cells of SS patients with low HbF. Leukemia3 (1989) 764a.
Croizat, H., and Nagel, R. L., Possible role of % HbF level and BPA production in the regulation of circulating SS-BFU-E population in sickle cell disease. Ann. N.Y. Acad. Sci. (1989) 373–378.
Croizat, H., and Nagel, R. L., Burst-promoting units of erythroid lineage have growth factor response heterogeneity in sickle cell anemia. Clin. Res.38 (1990) 389a.
Croizat, H., and Nagel, R. L., The circulating BFU-E in sickle cell anemia have different growth factor dependency according to HbF level of the patient. Blood76 (1990) 58a.
Croizat, H., and Nagel, R. L. Negative regulation may be involved in the proliferation of circulating BFU-E in SS patients. 16th A. Meeting Natl Sickle Cell Disease Program, Mobile, AL, 1991, p. 35.
Del Rizzo, D. F., Eskinazi, D., and Axelrad, A. A., Interleukin-3 opposes the action of negative regulatory protein (NRP) and of transforming growth factor-β (TGF-β) in their inhibition of DNA synthesis of the erythroid stem cell BFU-E. Exp. Hemat.8 (1990) 138–142.
Donahue, R. E., Emerson, S. G., Wang, E. A., Wong, G. G., Clark, S. C., and Nathan, D. G., Demonstration of burst promoting activity of recombinant human GM-CSF on circulating erythroid progenitors using an assay involving the delayed addition of erythropoietin. Blood66 (1985) 1479–1481.
Dover, G. J., Smit, K. D., Chang, Y. C., Purvis, S., Mays, A., Meyers, D. A., Sheils, C., and Serjeant, G., Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2. Blood80 (1992) 816–824.
Duncan, E., Laver, J., Abboud, M., Warren, D., Manniatis, M., Bussel, J., Auld, P., and Moore, M. A. S., Plasma G-GM-CSF levels in normal full term neonates: Correlation with high numbers of circulating hematopoietic progenitors. Blood72 (1988) 368a.
Eaves, C. J., Humphries, R. K. and Eaves, A. C., In vitro characterization of erythroid precursor cells and the erythropoietic differentiation process, in: Cellular and Molecular Regulation of Hemoglobin Switching, pp. 251–273. Eds G. Stamatoyannopoulos and A. W. Nienhius. Grunne-Stratton, New York 1979.
Ema, H., Suda, T., Nagayoshi, K., Miura, Y., Civin, C. L., and Nakauchi, H., Target cells for granulocyte colony-stimulating factor, Interleukin-3 and Interleukin-5 in differentiation pathways of neutrophils and eosinophiles. Blood76 (1990) 1956–1961.
Embury, S. H., Dozy, A. M., Miller, J., Davis, J. R., Kleman, K. M., Presiler, H., Vichinsky, E., Lande, W. N., Lubin, B., Kan, Y. W., and Mentzer, W. C., Concurrent sickle-cell anemia and α-thalassemia. Effect on severity of anemia. N. Engl. J. Med.306 (1982) 270–274.
Emerson, S. G., Thomas, S., Ferrara, J. L., and Greenstein, J. L., Developmental regulation of erythropoiesis by hematopoietic growth factors: Analysis on populations of BFU-E from bone marrow, peripheral blood, and fetal liver. Blood74 (1989) 49–55.
Golde, D. W., and Cline, M. J., Identification of the colony-stimulating cell in human peripheral blood. J. clin. Invest.51 (1972) 2982–2983.
Goldwasser, E., Ihle, J. N., Prystowsky, M. B., Rich, I., and van Zant, G., The effect of interleukin-3 on hemopoietic precurssor cells, in: Normal and Neoplastic Hematopoiesis, pp. 301–309. Alan R. Liss, New York 1983.
Gregory, C. J., and Eaves, A. C., Three stages of crythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properites. Blood51 (1978) 527–537.
Higgs, D. R., Aldridge, B. E., Lamb, J., Clegg, J. B., Weatherall, D. J., Hayes, R. J., Grandison, Y., Lowrie, Y., Maon, K. P., Serjeant, B. E., and Serjeant, G. R., The interaction of alpha-thalassemia and homozygous sickle cell disease. N. Engl. J. Med.306 (1982) 1441–1446.
Hirano, T., Yasukawa, K., Harada, H., Taga, T., Watanae, Y., Matsuda, T., Kashiwamura, S., Nakajima, K., Koyma, K., Iwamatsu, A., Tsunasawa, S., Sakiyama, F., Matsui, H., Takahara, Y., Taniguchi, T., and Kishimoto, T., Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature324 (1986) 73–76.
Ihle, J. N., Keller, J., Oroszlan, S., Henderson, L. E., Copeland, T. D., Fitch, F., Prystowsky, M. B., Goldwasser, E., Schrader, J. W., Palaszynski, E., Dy, M., and Lebel, B., Biological properties of homogenous interleukin 3. I. Demonstration of WEHI-3 growth factor activity, mast cell growth factor activity, P cell-stimulating factor activity, colony-stimulating factor activity, and histamine-producing cell-stimulating factor activity. J. Immuno.131 (1983) 282–287.
Javid, J., and Pettis, P. K., Fetal hemoglobin accumulation. In Vitro effect of adherent mononuclear cells. J. clin. Invest.71 (1983) 1358–1365.
Johnson, G. R., Begley, C. G., and Matthews, R. N., Transfusion dependent β-thalassemia: in vitro characterization of peripheral blood multipotential and committed progenitor cells. Exp. Hemat.15 (1987) 394–405.
Koike, K., Ogawa, M., Ihle, N., Miyake, T., Shimizu, T., Miyajima, A., Yokota, T., and Arai, K., J. Cell Physiol.131 (1987) 458–464.
Lee, M., Segal, M. G., and Bagby, G. C., Interleukin-1 induces human bone marrow derived fibroblasts to produce multilineage hematopoietic growth factors. Exp. Hemat.15 (1987) 983–988.
Lipton, J. M., Link, N. A., Breard, J., Jackson, P. L., Clarke, B. J., and Nathan, D. G., Monocytes do not inhibit peripheral blood erythroid burst forming unit colony formation. J. clin. Invest.65 (1980) 219–223.
Lutton, J. D., Schmalzer, E. A., Rao, A. N., Rao, S. P., and Levere, R. D., Erythroid colony studies on sickle all anemia in hypoproliferative crisis. Am. J. Hemat.8 (1980) 15–21.
Mangan, K. F., and DesForges, J. F., The role of T-lymphocytes and monocytes in the regulation of human erythropoietic peripheral blood burst forming units. Exp. Hemat.8 (1980) 717–727.
March, C. J., Mosley, B., Larsen, A., Cerretti, D. N., Braedt, G., Price, V., Gillis, S., Henney, C. S., Kronheim, S. R., Grabstein, K., Conlon, P. J., Hopp, T. D., and Cosman, D., Cloning, sequence and expression of two distinct human Interleukin-1 complementary DNAs. Nature315 (1985) 641–647.
Martin, F. H., Suggs, S. V., Langley, K. E., Lu, H. S., Ting, J., Okino, K. H., Morris, F. C., McNiece, I. K., Jacobsen, F. W., Mendiaz, E. A., Birkett, N. C., Smith, K. A., Johnson, M. J., Parker, V. P., Flores, J. C., Patel, A. C., Fisher, E. F., Erjavec, H. O., Herrera, C. J., Wypych, J., Sachdev, R. K., Pope, J. A., Leslie, I., Wen, D., Lin, C-H, Cupples, R. L., and Zsebo, K. M., Primary structure and functional expression of rat and human stem cell factor DNAs. Cell63 (1990) 203–211.
Metcalf, D., Haemopoietic growth factors. I. Lancet15 (1989) 825–827.
Metcalf, D., Johnson, G. R., and Burgess, A. W., direct stimulation by purified GM-CSF of the proliferration of multipotential and erythroid percursor cells. Blood55 (1980) 138–147.
Moore, M. A. S., Clinical implications of positive and negative hematopoietic stem cell regulators. Blood78 (1991) 1–19.
Mulligan, T., Guba, S., and Emerson, S. G., Unstimulated bone marrow stromal cells secrete multiple hematopoietic growth factors, detection by serum free progenitor cell proliferation. Blood74 (1989) 554a.
Munker, R., Gasson, J., Ogawa, M., and Koeffler, H. P., Recombinant human TNF induces production of granulocytemonocyte colony stimulating factor. Nature323 (1986) 79–82.
Nathan, D. G., and Alter, B. P., F-cell regulation. Ann. N.Y. Acad. Sci.344 (1980) 219.
Nissen, C., Iscove, N. N. and Speck, B., High burst-promoting activity (BPA) in serum of patients with acquired aplastic anemia, in: In Vitro Aspects of Erythropoiesis, pp. 79–87. Ed. M. J. Murphy. Springer Verlag, New York 1979.
Ogawa, M., Grush, O. C., O'Dell, R. F., Hara, H., and MacEacheren, M. D., Circulating erythropoietic precursors assessed in cultures. Characterization in normal men and patients with hemoglobinopathies. Blood50 (1977) 1081–1093.
Pagnier, J., Mears, J. G., Dunda-Belkodja, O., Schaefer-Rego, K. E., Beldjord, C., Nagel, R. L., and Labie, D., Common haplotype dependency of highGγ-globin gene expression and high HbF levels in β-thalassemia and sickle cell anemia patients. Proc. natl Acad. Sci. USA81 (1984) 1771–1773.
Pennathus-Das, R., Alpen, E., Vichinsky, E., Garcia, J., and Lubin, B., Evidence for the presence of CFU-E with increased in vitro sensitivity to erythropoietin in sickle cell anemia. Blood63 (1984) 1168–1171.
Rinehart, J. J., Zanjani, E. D., Breard, J., Jackson, P. L., Clark, B. J., and Nathan, D. G., Cell-cell interaction in erythropoiesis. Role of human monocytes. J. clin. Invest.62 (1978) 979–986.
Shechter-Levin, S., Amato, D., Karrass, L., and Axelrad, A. A., Heterogeneity of buoyant density and proliferative state of circulating erythropoietic progenitor cells (BFU-E) in man. Exp. Hemat.13 (1985) 1138–1142.
Sonoda, Y., Yang, Y., Wong, G. G., Clark, S. C., and Ogawa, M., Analysis in serum-free culture of the targets of recombinant human hemopoietic growth-factors: Interlukin 3 and granulocyte/macrophage-colony-stimulating factor are specific for early developmental stages. Proc. natl Acad. Sci. USA85 (1988) 4360–4364.
Sporn, M. B., and Roberts, A. B., Transforming growth factor-β: Multiple actions and potential clinical applications. J. Am. med. Assoc.262 (1989) 938–941.
Takeichi, N., Umemura, T., Katsuno, M., Nishimura, J., Motomura, S., and Ibayashi, H., Regulatory roles of burst-promoting activity (BPA) from bone marrow cells during human regenerating hemopoiesis. Exp. Hemat.15 (1987) 790–796.
Weinberg, R. S., Giardina, P., and Alter, B. P., Characteristics of erythroid progenitor cells in β-thalassemia major and β-thalassemia intermedia. Ann. N.Y. Acad. Sci.612 (1990) 536–537.
Weinberg, R. S., He., L., and Alter, B. P., Erythropoiesis is distinct at each stage of ontogeny. Pediatr. Res. (1992) in press.
Williams, D. E., Eisenman, J., Baird, A., Rauch, C., van Ness, K., March, C. J., Park, L. S., Martin, U., Mochizuki, D. Y., Boswell, H. S., Burgess, G. S., Cosman, D., and Lyman, S. D., Identification of a ligand for the c-kit proto-oncogene. Cell63 (1990) 167–174.
Wimperis, J. Z., Niemeyer, C. M., Sieff, C. A., Mathey-Prevot, B., Nathan, D. G., and Arcecr, R. J., Granulocytemacrophage colony stimulating factor and interleukin-3 mRNAs are produced by a small fraction of blood mononuclear cells. Blood74 (1989) 1525–1530.
Wong, G. G., Witeck, J. S., Temple, P. A., Wilkens, K. M., Leary, A. C., Luxenberg, D. P., Jones, S. S., Brown, E. L., Kay, R. M., Orr, E. C., Shoemaker, C., Golde, D. W., Kaufman, R. J., Hewick, R. M., Clark, S. C., and Wang, E. A., Molecular cloning of human and gibbon T-cell derived GM-CSF cDNAs and purification of the natural and recombinant proteins, in: Cancer Cells, vol. 3, Growth Factors and Transformation, pp. 235–242. Eds J. Feramisco, B. Ozanne and Stilles. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 1985B.
Wong, G. G., Witek, J. S., Temple, P. A., Wilkens, K. M., Leary, A. C., Luxenberg, D. P., Jones, S. S., Brown, E. L., Kay, R. M., Orr, E. C., Shoemaker, C., Golde, D. W., Kaufman, R. J., Hewick, R. M., Wang, E. A., and Clark, S. C., Human GM-CSF: Molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science228 (1985) 810–815.
Yang, Y. C. H., Ciarletta, A. B., Templa, P. A., Chung, M. P., Kovacic, S., Witek-Giannotti, J. S., Leary, A. C., Kriz, R., Donahue, R. E., Wong, G. G., and Clark, S. C., Human 1L-3 (multi-CSF) identification by expression cloning of a novel hematopoietic growth factor related to murine 1L-3. Cell47 (1986) 3–10.
Yokota, T., Otsuka, T., Mosmann, T., Bancheneau, J., DeFrance, T., Blanchard, D., DeVries, J. E., Lee, F., and Arai, K. I., Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B cell stimulatory factor 1, that express B cell- and T-cell-stimulating activities. Proc. natl Acad. Sci. USA83 (1986) 5894–5898.
Zsebo, K., Yuschenkoff, Y., Fox, M., Schiffer, S., McCall, E., Chang, D., Bagby, G., and Altrock, B., Interleukin-1 stimulates the production of Gm-CSF and GM-CSF by endothelial cells in-vitro. Blood, Suppl.68 (1986) 620.
Zucali, J. R., Broxmeyer, H. E., Dinarello, C. A., Gross, M. A., and Weiner, R. S., Regulation of early human hematopoietic (BFU-E and CFU-GEMM) progenitor cells in vitro by interleukin 1-induced fibroblast-conditioned medium. Blood69 (1987) 33–37.
Zucali, J. R., Dinarello, C. A., Oblon, D. J., Gross, M. A., Anderson, L., and Weiner, R. S., Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony stimulating activity (GM-CSA) and prostaglandin E2 (PGE2). J. clin. Invest.77 (1986) 1857–1863.
Zuckerman, K. S., Human erythroid burst-forming units. Growth in vivo is dependent on monocytes. but not T-lymphocytes. J. clin. Invest.67 (1981) 702–709.
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Croizat, H. Early circulating erythroid progenitors (BFU-E) in sickle cell anemia. Experientia 49, 118–125 (1993). https://doi.org/10.1007/BF01989415
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DOI: https://doi.org/10.1007/BF01989415