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Titolo:
Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways
Autore:
Mizuki, M; Fenski, R; Halfter, H; Matsumura, I; Schmidt, R; Muller, C; Gruning, R; Kratz-Abers, K; Serve, S; Steur, C; Buchner, T; Kienast, J; Kanakura, Y; Berdel, WE; Serve, H;
Indirizzi:
Univ Munster, Med Klin, Dept Med Hematol & Oncol, D-48129 Munster, GermanyUniv Munster Munster Germany D-48129 l & Oncol, D-48129 Munster, Germany Univ Munster, Dept Neurol, D-48129 Munster, Germany Univ Munster MunsterGermany D-48129 pt Neurol, D-48129 Munster, Germany Osaka Univ, Sch Med, Dept Hematol & Oncol, Suita, Osaka 565, Japan Osaka Univ Suita Osaka Japan 565 Hematol & Oncol, Suita, Osaka 565, Japan
Titolo Testata:
BLOOD
fascicolo: 12, volume: 96, anno: 2000,
pagine: 3907 - 3914
SICI:
0006-4971(200012)96:12<3907:FMFPWA>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
INTERNAL TANDEM DUPLICATION; RECEPTOR TYROSINE KINASE; HEMATOPOIETIC PROGENITOR CELLS; HUMAN BONE-MARROW; C-KIT; CONSTITUTIVE ACTIVATION; GROWTH-FACTOR; HUMAN HOMOLOG; MURINE FLT3; STEM-CELLS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Serve, H Univ Munster, Med Klin, Dept Med Hematol & Oncol, Albert Schweitzer Str 33, D-48129 Munster, Germany Univ Munster Albert Schweitzer Str 33 Munster Germany D-48129 ny
Citazione:
M. Mizuki et al., "Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways", BLOOD, 96(12), 2000, pp. 3907-3914

Abstract

Somatic mutations of the receptor tyrosine kinase Flt3 consisting of internal tandem duplications (ITD) occur in 20% of patients with acute myeloid leukemia. They are associated with a poor prognosis of the disease. In this study, we characterized the oncogenic potential and signaling properties ofFlt3 mutations. We constructed chimeric molecules that consisted of the murine Flt3 backbone and a 510-base pair human Flt3 fragment, which containedeither 4 different ITD mutants or the wild-type coding sequence, Flt3 isoforms containing ITD mutations (Flt3-ITD) induced factor-independent growth and resistance to radiation-induced apoptosis in 32D cells. Cells containing Flt3-ITD, but not those containing wild-type Flt3 (Flt3-WT), formed colonies in methylcellulose. Injection of 32D/Flt3-ITD induced rapid developmentof a leukemia-type disease in syngeneic mice. Flt3-ITD mutations exhibitedconstitutive autophosphorylation of the immature form of the Flt3 receptor. Analysis of the involved signal transduction pathways revealed that Flt3-ITD only slightly activated the MAP kinases Erk1 and 2 and the protein kinase B (Akt) in the absence of ligand and retained ligand-induced activation of these enzymes, However, Flt3-ITD led to strong factor-independent activation of STAT5. The relative importance of the STAT5 and Ras pathways for ITD-induced colony formation was assessed by transfection of dominant negative (dn) forms of these proteins: transfection of dnSTAT5 inhibited colony formation by 50%, Despite its weak constitutive activation by Flt3D-ITD, dnRas also strongly inhibited Flt3-ITD-mediated colony formation. Taken together, Flt3-ITD mutations induce factor-independent growth and leukemogenesis of 32D cells that are mediated by the Ras and STAT5 pathways. (C) 2000 by The American Society of Hematology.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/21 alle ore 00:45:58