Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25)

Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangem ent of the ETV6/TEL gene. Applying the fluorescence in situ hybridization ( FISH) method, we found a cryptic translocation t(12;15)(p13;q25) in an adul t acute myeloid leukemia (AML) patient. Hybridization with cosmid probes sh owed that the ETV6 gene was rearranged in this translocation. A patient-spe cific cDNA library was screened with ETV6 cDNA, and a novel fusion transcri pt was identified between the ETV6 and TRKC/NTRK3 gene located on 15q25. TR KC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3) . It is known to be expressed broadly in neural tissues but not in hematolo gic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) dom ain of the TRKC gene. Two types of fusion transcript were determined, one t hat included the entire PTK domain of TRKC and the other in which the 3'-te rminal 462 bp of TRKC was truncated within the PTK domain. Western blot ana lysis showed the expression of both chimeric proteins of 52 and 38 kD in si ze. Our results suggest that chimeric PTK expressed in the leukemic cells m ay contribute to cellular transformation by abnormally activating TRK signa ling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia. (C) 1999 by The American Society of Hema tology.