Expression of RET receptor tyrosine kinase and GDNFR-α in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment

Valter Gattei, Angela Celetti, Aniello Cerrato, Massimo Degan, Angela De Iuliis, Francesca Maria Rossi, Gennaro Chiappetta, Claudia Consales, Salvatore Improta, Vittorina Zagonel, Donatella Aldinucci, Valter Agosti, Massimo Santoro, Giancarlo Vecchio, Antonio Pinto, Michele Grieco

Research output: Contribution to journalArticle

Abstract

The RET proto-oncogene products 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-α) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-α 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 and 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-α, which detected only in 2 isolated primary samples and 3 leukemia/lymphoma cell lines. However, GDNFR-α transcripts, in the absence of RET mRNA, were found in normal bone marrow stromal cells (BMSC), in BM fibroblasts, and it 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.

Original languageEnglish
Pages (from-to)2925-2937
Number of pages13
JournalBlood
Volume89
Issue number8
Publication statusPublished - Apr 15 1997

ASJC Scopus subject areas

  • Hematology

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    Gattei, V., Celetti, A., Cerrato, A., Degan, M., De Iuliis, A., Rossi, F. M., Chiappetta, G., Consales, C., Improta, S., Zagonel, V., Aldinucci, D., Agosti, V., Santoro, M., Vecchio, G., Pinto, A., & Grieco, M. (1997). Expression of RET receptor tyrosine kinase and GDNFR-α in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment. Blood, 89(8), 2925-2937.