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Title: Fluorescence in situ hybridization (FISH) study of response to granulocyte colony stimulating factor (G-CSF) in myelodysplasia associated with monosomy 7: Evidence for differentiation of the dysplastic clone

Abstract

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic differentiation which may respond to the administration of cytokines with increases in the number of circulating mature neutrophils. We used fluorescence in situ hybridization (FISH) to investigate a young patient with myelodyplasia associated with monosomy 7 to determine whether mature appearing polymorphonuclear cells present in response to treatment with granulocyte colony stimulating factor (G-CSF) were progeny of the dysplastic clone or represented stimulation of residual normal hematopoiesis. The patient is a 26 year old male with a long history of a complex stem cell disorder dating to age 5. A chromosome fragility test was negative. In October 1993 treatment was begun with G-CSF when the absolute neutrophil count (ANC) fell to 300/mm{sup 3} despite GM-CSF therapy. Cytogenetic study of bone marrow just prior to starting G-CSF revealed monosomy 7 in all metaphases. A study in July, 1992 was normal. On his most recent marrow examination (1/94), blasts had numerous dysplastic forms. FISH was performed on buffy coat smears of patient and control specimens using a biotin labelled alpha satellite probe to chromosome 7. At the time of study, the peripheral blood count was 12,500 mm{sup 3}, with 56% neutrophils, 6% bands andmore » no circulating blasts. Cells were scored as either polymorphonuclear or mononuclear cells. In a healthy control, 22 of 190 scored as either polymorphonuclear cells (12%) contained one chromosome 7 signal, versus 193 of 200 (96.5%) in the patient. For mononuclear cells, the control demonstrated 23 of 137 nuclei (17%) with one signal, versus 300 of 511 nuclei (59%) in the patient. We conclude that G-CSF induced differentiation in the dysplastic clone in this case and did not stimulate normal hermatopoiesis.« less

Authors:
 [1]; ;  [2]
  1. Rhode Island Hospital, Providence, RI (United States)
  2. Brown Univ. School of Medicine, Providence, RI (United States)
Publication Date:
OSTI Identifier:
133484
Report Number(s):
CONF-941009-
Journal ID: AJHGAG; ISSN 0002-9297; TRN: 95:005313-0212
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; Journal Volume: 55; Journal Issue: Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; PATIENTS; BLOOD FORMATION; HEMIC DISEASES; HUMAN CHROMOSOME 7; DNA-CLONING; CHROMOSOMAL ABERRATIONS; DNA HYBRIDIZATION; FLUORESCENCE; HEMATOPOIETIC SYSTEM; LEUKOCYTES; PROBES

Citation Formats

Cicilline, M., Mark, H.F.L., and Rintels, P. Fluorescence in situ hybridization (FISH) study of response to granulocyte colony stimulating factor (G-CSF) in myelodysplasia associated with monosomy 7: Evidence for differentiation of the dysplastic clone. United States: N. p., 1994. Web.
Cicilline, M., Mark, H.F.L., & Rintels, P. Fluorescence in situ hybridization (FISH) study of response to granulocyte colony stimulating factor (G-CSF) in myelodysplasia associated with monosomy 7: Evidence for differentiation of the dysplastic clone. United States.
Cicilline, M., Mark, H.F.L., and Rintels, P. Thu . "Fluorescence in situ hybridization (FISH) study of response to granulocyte colony stimulating factor (G-CSF) in myelodysplasia associated with monosomy 7: Evidence for differentiation of the dysplastic clone". United States. doi:.
@article{osti_133484,
title = {Fluorescence in situ hybridization (FISH) study of response to granulocyte colony stimulating factor (G-CSF) in myelodysplasia associated with monosomy 7: Evidence for differentiation of the dysplastic clone},
author = {Cicilline, M. and Mark, H.F.L. and Rintels, P.},
abstractNote = {Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic differentiation which may respond to the administration of cytokines with increases in the number of circulating mature neutrophils. We used fluorescence in situ hybridization (FISH) to investigate a young patient with myelodyplasia associated with monosomy 7 to determine whether mature appearing polymorphonuclear cells present in response to treatment with granulocyte colony stimulating factor (G-CSF) were progeny of the dysplastic clone or represented stimulation of residual normal hematopoiesis. The patient is a 26 year old male with a long history of a complex stem cell disorder dating to age 5. A chromosome fragility test was negative. In October 1993 treatment was begun with G-CSF when the absolute neutrophil count (ANC) fell to 300/mm{sup 3} despite GM-CSF therapy. Cytogenetic study of bone marrow just prior to starting G-CSF revealed monosomy 7 in all metaphases. A study in July, 1992 was normal. On his most recent marrow examination (1/94), blasts had numerous dysplastic forms. FISH was performed on buffy coat smears of patient and control specimens using a biotin labelled alpha satellite probe to chromosome 7. At the time of study, the peripheral blood count was 12,500 mm{sup 3}, with 56% neutrophils, 6% bands and no circulating blasts. Cells were scored as either polymorphonuclear or mononuclear cells. In a healthy control, 22 of 190 scored as either polymorphonuclear cells (12%) contained one chromosome 7 signal, versus 193 of 200 (96.5%) in the patient. For mononuclear cells, the control demonstrated 23 of 137 nuclei (17%) with one signal, versus 300 of 511 nuclei (59%) in the patient. We conclude that G-CSF induced differentiation in the dysplastic clone in this case and did not stimulate normal hermatopoiesis.},
doi = {},
journal = {American Journal of Human Genetics},
number = Suppl.3,
volume = 55,
place = {United States},
year = {Thu Sep 01 00:00:00 EDT 1994},
month = {Thu Sep 01 00:00:00 EDT 1994}
}
  • We have attempted to evaluate in vivo effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on acute radiation hematopoietic injury in mice. BDF1 mice, irradiated with 7.5-Gy x-rays, were injected i.p. twice daily for 10 days with 10(5) U recombinant human G-CSF, 3.75 x 10(5) U recombinant murine GM-CSF, or a combination of both. G-CSF significantly enhanced the recovery of not only peripheral leukocytes but also platelets and hematocrit on days 14 and 21 after irradiation. GM-CSF significantly enhanced the recovery of platelets on day 14 and peripheral leukocytes on day 21. G-CSF markedly enhanced the recoverymore » of spleen colony-forming units (CFU-S), colony-forming units in culture (CFU-C), erythroid burst-forming units (BFU-E), and megakaryocyte colony-forming units (CFU-Meg) both in bone marrow and in the spleen. GM-CSF significantly enhanced the recovery of CFU-Meg in bone marrow on day 14. We found synergistic effects between G-CSF and GM-CSF on CFU-S, CFU-C, and CFU-Meg in the spleen on day 14, although we found antagonistic effects between G-CSF and GM-CSF on CFU-S and CFU-C in bone marrow on day 7, and on platelet counts on day 7. These results indicate that the administration of recombinant G-CSF and GM-CSF may be useful in accelerating hematopoietic recovery in patients with acute radiation hematopoietic injuries.« less
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  • Using the mouse interleukin 3 (IL-3) receptor cDNA as a probe, the authors obtained a monologous cDNA (KH97) from a cDNA library of a human hemopoietic cell line, TF-1. The protein encoded by the KH97 cDNA has 56% amino acid sequence identity with the mouse IL-3 receptor and retains features common to the family of cytokine receptors. Fibroblasts transfected with the KH97 cDNA expressed a protein of 120 kDa but did not bind any human cytokines, including IL-3 and granulocyte - macrophage colony-stimulating factor (GM-CSF). Interestingly, cotransfection of cDNAs for KH97 and the low-affinity human GM-CSF receptor in fibroblasts resultedmore » in formation of a high-affinity receptor for GM-CSF. The dissociation rate of GM-CSF from the reconstituted high-affinity receptor was slower than that from the low-affinity site, whereas the association rate was unchanged. Cross-linking of {sup 125}I-labeled GM-CSF to fibroblasts cotransfected with both cDNAs revealed the same cross-linking patterns as in TF-1 cells - i.e., two major proteins of 80 and 120 kDa which correspond to the low-affinity GM-CSF receptor and the KH97 protein, respectively. These results indicate that the high-affinity GM-CSF receptor is composed of at least two components in a manner analogous to the IL-2 receptor. They therefore propose to designate the low-affinity GM-CSF receptor and the KH97 protein as the {alpha} and {beta} subunits of the GM-CSF receptor, respectively.« less
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