Absence of mutations in the RET gene in acute myeloid leukemia

Abstract

Expression of the tyrosine kinase receptor RET has previously been detected in normal hematopoietic cells, and especially in cells of the myeloid lineage. Furthermore, RET was shown to be differentially expressed in acute myeloid leukemia (AML), a disease characterized by excessive cell growth and aberrant maturation of cells, with the highest levels of expression in leukemias with monocytic differentiation. RET is known to be expressed in cells from the excretory system and from the developing central and peripheral nervous system. Both activating and inactivating aberrations in the RET gene have been detected in disorders derived from these tissues. To investigate whether the differential expression is a primary defect in AML, the presence of RET alterations was scanned by Southern blot analysis on DNA of blasts obtained from 17 AML patients. However, no RET gene aberrations were found. Subsequently, denaturing gradient gel electrophoresis (DGGE) analysis was performed on the DNA of blasts from ten selected cases. All five variants detected turned out to represent neutral DNA polymorphisms, including a novel polymorphism in exon 14. Since we were unable to detect mutations of RET in AML, it is unlikely that it plays an important role in leukemogenesis.

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

“…Somatic and germ-line RET mutations leading to gene activation are responsible for several human diseases, including multiple endocrine neoplasia types 2A and 2B and papillary thyroid carcinomas (24). Nevertheless, mutations of RET as a mechanism of overexpression were discarded in the present MYST3-CREBBP series, in accordance with a previous study analyzing diverse AML subtypes (33). One of the most striking findings of this study was the similarities observed between MYST3-CREBBP and MLL-rearranged leukemias.…”

“…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).…”

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

“…In this regard, the coexpression, demonstrated here, by RETexpressing leukaemic cells of specific adhesion molecules capable to mediate interactions of myeloid blasts with the bone marrow microenvironment (Bradstock & Gottlieb, 1995) may represent additional mechanism(s) favouring the 'physiological' cross-talk of RET, as expressed by AML blasts, with GDNF and GDNFR-a, in turn provided by stromal and accessory cells. Such a model is in agreement with a recent finding that no RET gene structural aberrations and activating mutations can be found in AMLs (Visser et al, 1997). Interestingly, this seems to be in apparent contrast with the high rate of activating point mutation of the RET gene found in other non-haemopoietic malignancies (Eng, 1996), but is consistent with the overall absence of functionally active point mutations of other haemopoietic RTKs, including C-KIT and C-FMS in AMLs (Springall et al, 1993;Arland et al, 1994).…”

RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation

“…A similar result was found in AML where the structure of RET was investigated by Southern blot and denaturing gradient gel electrophoresis in 17 patients. 22 The two RET fusion genes described here merge exon 12 of RET in 3 0 with BCR exon 4 or FGFR1OP exon 12 in 5 0 . The 5 0 part of the fusion genes encodes dimerization domains, in a similar way to all the fusion gene partners reported in papillary thyroid, lung and colorectal carcinomas associated with RET rearrangements (PTC1…”