Document Detail


Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment.
MedLine Citation:
PMID:  9108413     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The RET proto-oncogene product is a receptor tyrosine kinase representing the signal-transducing molecule of a multisubunit surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), in which a novel glycosyl-phosphatidylinositol (PI)-linked protein (termed GDNFR-alpha) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-alpha in purified normal hematolymphopoietic cells, leukemia/lymphoma cell lines, and 154 primary samples from patients with hematopoietic malignancies encompassing different lineages and differentiation stages. Relatively low amounts of RET mRNA were found in early CD34+ hematopoietic progenitors, but RET transcripts appeared to increase after myelomonocytic maturation. No expression of RET was found in peripheral blood and tissue B and T lymphocytes. Analysis of human myelomonocytic cell lines was overall consistent with results obtained on purified normal cells. Accordingly, RET expression was mainly confined to acute myeloid leukemias (AMLs) displaying either monocytic (French-American-British M4 and M5) or intermediate-mature myeloid (M2 and M3) phenotypes, being less frequently detected in early myeloid (M0 and M1) AMLs. In contrast, RET mRNA was sporadically detected in B-cell tumors, whereas, among T-cell malignancies, RET transcripts were mainly detected in cells of postthymic and mature T-cell phenotype. RET broad detection in primary tumors was not paralleled by the mutual expression of GDNFR-alpha, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines. However, GDNFR-alpha transcripts, in the absence of RET mRNA, were found in normal bone marrow stromal cells (BMSC), in BM fibroblasts, and in two osteoblast cell lines previously described to support normal hematopoiesis. In the presence of GDNF-receptors derived from BMSC by PI-specific phospholipase C cleavage, GDNF efficiently bound RET-expressing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells.
Authors:
V Gattei; A Celetti; A Cerrato; M Degan; A De Iuliis; F M Rossi; G Chiappetta; C Consales; S Improta; V Zagonel; D Aldinucci; V Agosti; M Santoro; G Vecchio; A Pinto; M Grieco
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Blood     Volume:  89     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  1997 Apr 
Date Detail:
Created Date:  1997-05-19     Completed Date:  1997-05-19     Revised Date:  2012-06-04    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2925-37     Citation Subset:  AIM; IM    
Affiliation:
Divisione di Oncologia Medica, Centro di Riferimento Oncologico, INRCCS, Aviano, Italy.
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MeSH Terms
Descriptor/Qualifier:
Adipose Tissue / metabolism*,  pathology
Bone Marrow / metabolism*,  pathology
Connective Tissue / metabolism*,  pathology
Drosophila Proteins*
Gene Expression Regulation*
Gene Expression Regulation, Leukemic
Glial Cell Line-Derived Neurotrophic Factor Receptors
Hematologic Neoplasms / genetics,  metabolism,  pathology
Hematopoietic Stem Cells / metabolism*,  pathology
Humans
Leukemia / classification,  genetics,  metabolism*,  pathology
Lymphocyte Subsets / metabolism,  pathology
Myeloproliferative Disorders / genetics,  metabolism,  pathology
Neoplasm Proteins / biosynthesis*,  genetics
Neoplastic Stem Cells / metabolism*,  pathology
Proto-Oncogene Proteins / biosynthesis*,  genetics
Proto-Oncogene Proteins c-ret
RNA, Messenger / biosynthesis
RNA, Neoplasm / biosynthesis
Receptor Protein-Tyrosine Kinases / biosynthesis*,  genetics
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Drosophila Proteins; 0/Glial Cell Line-Derived Neurotrophic Factor Receptors; 0/Neoplasm Proteins; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/RNA, Neoplasm; EC 2.7.10.1/Proto-Oncogene Proteins c-ret; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 2.7.10.1/Ret oncogene protein, Drosophila

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