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Titolo:
Combined corticosteroid/granulocyte colony-stimulating factor (G-CSF) therapy in the treatment of severe congenital neutropenia unresponsive to G-CSF: Activated glucocorticoid receptors synergize with G-CSF signals
Autore:
Dror, Y; Ward, AC; Touw, IP; Freedman, MH;
Indirizzi:
Univ Toronto, Hosp Sick Children, Dept Pediat, Div Hematol & Oncol, Toronto, ON M5G 1X8, Canada Univ Toronto Toronto ON Canada M5G 1X8 Oncol, Toronto, ON M5G 1X8, Canada Univ Toronto, Hosp Sick Children, Res Inst, Toronto, ON M5G 1X8, Canada Univ Toronto Toronto ON Canada M5G 1X8 Inst, Toronto, ON M5G 1X8, Canada Erasmus Univ, Inst Hematol, Rotterdam, Netherlands Erasmus Univ Rotterdam Netherlands Inst Hematol, Rotterdam, Netherlands
Titolo Testata:
EXPERIMENTAL HEMATOLOGY
fascicolo: 12, volume: 28, anno: 2000,
pagine: 1381 - 1389
SICI:
0301-472X(200012)28:12<1381:CCCF(T>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
JUVENILE MYELOMONOCYTIC LEUKEMIA; TRANSCRIPTION FACTOR; POSSIBLE MECHANISM; EVI-1 GENE; GRANULOCYTE; CELLS; EXPRESSION; STAT3; DIFFERENTIATION; PROGENITORS;
Keywords:
Kostmann's disease; neutropenia; granulocyte colony-stimulating factor; glucocorticoids; receptor;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Freedman, MH Hosp Sick Children, Div Hematol Oncol, 555 Univ Ave, Toronto,ON M5G 1X8, Canada Hosp Sick Children 555 Univ Ave Toronto ON Canada M5G 1X8 ada
Citazione:
Y. Dror et al., "Combined corticosteroid/granulocyte colony-stimulating factor (G-CSF) therapy in the treatment of severe congenital neutropenia unresponsive to G-CSF: Activated glucocorticoid receptors synergize with G-CSF signals", EXP HEMATOL, 28(12), 2000, pp. 1381-1389

Abstract

Objective. More than 90% of patients with severe congenital neutropenia (SCN) respond to granulocyte colony-stimulating factor (G-CSF) therapy. The basis for the refractory state in the remaining patients is unknown. To address this issue, we studied a child with SCN who was totally unresponsive toG-CSF and had a novel point mutation in the extracellular domain of the G-CSF receptor (GCSF-R). Materials and Methods. Marrow stromal support of granulopoiesis was evaluated by plating CD34(+) cells on preformed stromal layers. Nonadherent cellswere harvested and assayed in clonogenic assays for granulocytic colony production. The in vitro effect of G-CSF and corticosteroids on granulopoiesis was evaluated in clonogenic assays of marrow mononuclear cells, by proliferation studies of the murine myeloid cell line 32D expressing the patient's mutated G-CSFR, and by measuring STAT5 activation in nuclear extracts from stimulated cells. Results. Patient's stroma supported granulopoiesis derived from control marrow CD34(+) cells in a normal manner. Normal stroma, however, failed to induce granulopoiesis from patient's CD34(+) cells. Clonogenic assays of the patient's marrow mononuclear cells incorporating either G-CSF or hydrocortisone produced little neutrophil growth, In contrast, inclusion of both G-CSF and hydrocortisone in the cytokine "cocktail" markedly increased the neutrophil numbers. Proliferation of 32D cells expressing the mutated receptor and STAT5 activation were improved by a combination of G-CSF and dexamethasone. When small daily doses of oral prednisone were then administered to the patient with conventional doses of subcutaneous G-CSF, the patient responded with increased neutrophil numbers and with a complete reversal of the infectious problems. Conclusions. These data provide insight into SCN unresponsive to standard G-CSF treatment and to the potential corrective action of combined treatment with G-CSF and corticosteroids through synergistic activation of STAT5. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 19:37:06