The RET receptor tyrosine kinase, but not its specific ligand, GDNF, is preferentially expressed by acute leukaemias of monocytic phenotype and is up-regulated upon differentiation

Abstract

Summary. The RET gene product represents the signaltransducing molecule of a surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), which includes GDNFR-a as a ligand-binding component. By a semi-quantitative competitive RT-PCR approach, we have analysed the relative abundances of RET transcripts in blasts purified from 40 acute myeloid leukaemia (AML) cases, revealing significant amounts of RET transcripts in 60% of AML cases (24/40). RT-PCR data was confirmed by immunocytochemical detection of RET protein in leukaemic blasts. The highest RET mRNA levels, almost exclusively confined to FAB M4/M5 AMLs, directly correlated with the presence on leukaemic cells of adhesion molecules and surface structures typically expressed by blasts of monocytic lineage and were inversely associated with the expression of the stem cell antigen CD34. Consistently, differentiation of the monoblastic cell line U937 resulted in an up-regulated expression of RET proto-oncogene, which was maximal upon exposure to agents inducing a more complete monocytic differentiation. Finally, while transcripts specific for GDNF and GDNFR-a were never found in leukaemic blasts, stromal cells of the haemopoietic microenvironment expressed, in the absence of RET, significant amounts of both GDNF and GDNFR-a. Our results suggest a role for RET in the functional regulation of AMLs through interactions with GDNF-and GDNFR-a-producing stromal cells.

Gene Expression Profiling of Acute Myeloid Leukemia with Translocation t(8;16)(p11;p13) and MYST3-CREBBP Rearrangement Reveals a Distinctive Signature with a Specific Pattern of HOX Gene Expression

“…Thus, genes such as PRL, C20orf103, RET, GGA2, ICSBP1, ITGA7, DAP, IRAK1, and PPARG were overexpressed almost exclusively in MYST3-CREBBP cases. Among those genes, PRL and RET have been occasionally reported to be involved in leukemogenesis (24)(25)(26)(27)(28)(29)(30)(31)(32)(33). In this regard, an increased expression of prolactin protein in blast populations has been observed in anecdotal cases of monocytic-lineage leukemia as well as in the eosinophilic cell line Eol-1 (25)(26)(27)(28)(29).…”

“…Interestingly, STAT5A and STAT5B genes were found to be significantly underexpressed in our MYST3-CREBBP AML samples, suggesting a negative regulatory effect between prolactin and STAT5 proteins. On its turn, RET gene is a proto-oncogene that encodes a tyrosine kinase receptor expressed during normal myelomonocytic differentiation and, accordingly, has been found to be predominantly expressed in AML of monocytic phenotype (30)(31)(32). Moreover, RET mRNA levels are typically low among immature CD34 + hemopoietic progenitors whereas overexpression of this protein has been associated with coexpression of adhesion molecules such as CD56 (30).…”

Glial cell line-derived neurotrophic factor influences proliferation of osteoblastic cells

“…This is a novel and interesting finding, as previous studies reported that only GDNF and GFRα1were present in two human osteosarcoma cell lines (Saos-2, MG63) and primary bone marrow stromal cells, but not RET (12). Thus this latter work had led to the conclusion that GDNF signaling in the bone marrow environment involved interaction with RET-expressing hematopoietic cells (13)(14). Previous studies have suggested that isolated cells from calvarial bones may behave differently than osteoblasts derived from long bones ((21-23)), which may reflect the mechanistically different processes by which the different structures in the skeleton develop (i.e.…”

“…along with GDNF in bone marrow stromal cells, RET proved to be absent in these cells (12)(13). However, GDNF/GFR1 complexes cleaved from the stromal cells were shown to elicit functional signaling through RET expressed on hematopoietic and leukemic cells suggesting a signaling pathway involving cell-cell interactions within the bone marrow environment (13)(14).…”

“…However, GDNF/GFR1 complexes cleaved from the stromal cells were shown to elicit functional signaling through RET expressed on hematopoietic and leukemic cells suggesting a signaling pathway involving cell-cell interactions within the bone marrow environment (13)(14). In this study we addressed the question whether GDNF may be involved in bone metabolism.…”