Fusion of ETV6 to Neurotrophin-3 Receptor TRKC in Acute Myeloid Leukemia With t(12;15)(p13;q25)

Abstract

Chromosome translocations involving band 12p13 are known to be involved in a variety of hematologic malignancies, some of them resulting in rearrangement 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 adult acute myeloid leukemia (AML) patient. Hybridization with cosmid probes showed that the ETV6 gene was rearranged in this translocation. A patient-specific cDNA library was screened with ETV6 cDNA, and a novel fusion transcript was identified between the ETV6 andTRKC/NTRK3 gene located on 15q25. TRKC 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 hematologic cells, so far. ETV6-TRKC chimeric transcript encoded the pointed (PNT) domain of the ETV6 gene that fused to the protein-tyrosine kinase (PTK) domain of the TRKC gene. Two types of fusion transcript were determined, one that included the entire PTK domain of TRKC and the other in which the 3′-terminal 462 bp of TRKC was truncated within the PTK domain. Western blot analysis showed the expression of both chimeric proteins of 52 and 38 kD in size. Our results suggest that chimeric PTK expressed in the leukemic cells may contribute to cellular transformation by abnormally activating TRK signaling pathways. Moreover, this is the first report on truncated neurotrophin receptors associated in leukemia.

Revisiting NTRKs as an emerging oncogene in hematological malignancies

“…2a). This was in contrast to the oncofusion described by Eguchi et al [52], where only the first four exons of ETV6 were fused to NTRK3.…”

“…Moreover, one fusion included the entire PTK domain (encoding a 52 kD protein), while the other variant involved a truncated PTK domain (encoding a 38 kD protein). However, both of these chimeric proteins lack a 42-base-pair exon near the C-terminus of the NTRK3 protein that was reported thereafter in the EN oncofusion found in cases of congenital fibrosarcoma [52]. In addition to the 42-base-pair stretch, the fusion found in congenital fibrosarcoma contains ETV6 exons 1-5 versus 1-4 that are seen in EN fusions found in acute myeloid leukemia (AML).…”

Lentiviral shRNA silencing of BDNF inhibits in vivo multiple myeloma growth and angiogenesis via down‐regulated stroma‐derived VEGF expression in the bone marrow milieu

“…( 38,39 ) Numerous studies have uncovered the critical role for neurotrophins and their receptors on neuronal and non‐neuronal tumor pathology, such as neuroblastoma, adenocarcinoma of the thyroid, pancreatic ductal adenocarcinoma, prostate cancer, and hematological malignancies of myeloid leukemia and multiple myeloma. ( 6,14,40–45 ) In this study, we demonstrated that BDNF activation of TrkB mediates myeloma–BMSC interaction in the BM milieu, and promotes angiogenesis by elevating VEGF secretion in BMSCs. This is analogous to the effect of the BDNF/TrkB pathway in neuroblastoma.…”

GENETIC PROFILEOF ACUTE MYELOID LEUKEMIA

“…As shown below, ETV6 displays different functions in the different fusion transcripts (Fig 6). The t(1; 12) (q21; p13) and the t(12; 15) (p13; q25) are rare ETV6 translocations in myeloid disorders (57, 58). The t(1; 12) results in the ETV6/ARNT chimeric protein containing the 5′ end of ETV6 and almost all the aryl hydrocarbon receptor nuclear translocator (ARNT) protein.…”