The RET proto-oncogene product is a receptor tyrosine ki- nase representing the signal-transducing molecule of a multisubunit surface receptor complex for the glial cell line- derived neurotrophic factor (GDNF), in which a novel glyco- syl-phosphatidylinositol (PI)-linked protein (termed GDNFR- a) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-a in purified normal hemato- lymphopoietic cells, leukemia/lymphoma cell lines, and 154 primary samples from patients with hematopoietic malig- nancies 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) dis- playing either monocytic (French-American-British M4 and M5) or intermediate-mature myeloid (M2 and M3) pheno- types, being less frequently detected in early myeloid (M0 and M1) AMLs. In contrast, RET mRNA was sporadically de- tected 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 pri- mary tumors was not paralleled by the mutual expression of GDNFR-a, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines. However, GDNFR-a 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 de- scribed to support normal hematopoiesis. In the presence of GDNF-receptors derived from BMSC by PI-specific phos- pholipase C cleavage, GDNF efficiently bound RET-express- ing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells.
Expression of the RET receptor tyrosine kinase and GDNF-Ra in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow mic
ACeletti;
1997
Abstract
The RET proto-oncogene product is a receptor tyrosine ki- nase representing the signal-transducing molecule of a multisubunit surface receptor complex for the glial cell line- derived neurotrophic factor (GDNF), in which a novel glyco- syl-phosphatidylinositol (PI)-linked protein (termed GDNFR- a) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-a in purified normal hemato- lymphopoietic cells, leukemia/lymphoma cell lines, and 154 primary samples from patients with hematopoietic malig- nancies 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) dis- playing either monocytic (French-American-British M4 and M5) or intermediate-mature myeloid (M2 and M3) pheno- types, being less frequently detected in early myeloid (M0 and M1) AMLs. In contrast, RET mRNA was sporadically de- tected 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 pri- mary tumors was not paralleled by the mutual expression of GDNFR-a, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines. However, GDNFR-a 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 de- scribed to support normal hematopoiesis. In the presence of GDNF-receptors derived from BMSC by PI-specific phos- pholipase C cleavage, GDNF efficiently bound RET-express- ing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
