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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
V Gattei, A Celetti, A Cerrato, M Degan, A De Iuliis, FM Rossi, G Chiappetta, C Consales, S Improta, V Zagonel, D Aldinucci, V Agosti, M Santoro, G Vecchio, A Pinto and M Grieco
Divisione di Oncologia Medica, Centro di Riferimento Oncologico, INRCCS,
Aviano, Italy.
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.
Volume 89,
Issue 8,
pp. 2925-2937,
04/15/1997
Copyright © 1997 by The American Society of Hematology
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