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

The RET gene product represents the signal-transducing molecule of a surfac e receptor complex for the glial cell line-derived neurotrophic factor (GDN F), which includes GDNFR-alpha as a ligand-binding component. By a semi-qua ntitative competitive RT-PCR approach, we have analysed the relative abunda nces 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 o f RET protein in leukaemic blasts. The highest RET mRNA levels, almost excl usively confined to FAB M4/M5 AMLs, directly correlated with the presence o n leukaemic cells of adhesion molecules and surface structures typically ex pressed by blasts of monocytic lineage and were inversely associated with t he 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 m ore complete monocytic differentiation. Finally, while transcripts specific for GDNF and GDNFR-alpha were never found in leukaemic blasts, stromal cel ls of the haemopoietic microenvironment expressed, in the absence of RET, s ignificant amounts of both GDNF and GDNFR-alpha. Our results suggest a role for RET in the functional regulation of AMLs through interactions with GDN F- and GDNFR-alpha-producing stromal cells.