FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation

Abstract

The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.

Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

“…27 We also observed an increase in eosinophils in the 18-month old transgenic mice (267/ml, n ¼ 11) compared with the wild-type controls (156/ml, n ¼ 5), but this difference was not statistically significant (P ¼ 0.35, Figure 3c). No difference in the number of basophils was observed between the transgenic and wild-type mice (50/ml and 41/ml respectively, P ¼ 0.80) (Figure 3d).…”

“…25,26 Recently, a similar fusion of Tel-FLT3 was observed in a patient with myeloproliferative disorder. 27 The Tel-FLT3 fusion we constructed shares a high degree of structural similarity with the fusion seen in this patient: the intact HLH domain of Tel at the N-terminus fused to the tyrosine kinase domain of FLT3 at the C-terminus. Both of the fusion proteins confer constitutive activation on FLT3 and induce factor-independent growth in transfected Ba/F3 cells.…”

A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia

“…34,35 In addition, a TEL-FLT3 fusion has been reported in which the JM domain of FLT3 is disrupted. 36 Thus, the chromosomal break in the juxtamembrane domain may also alleviate the inhibitory conformation of CSF1R.…”

t(12;13)(p13;q12) ETV6/FLT3

“…In three patients, the ETV6/FLT3 implication was found (Vu et al, 2006;Walz et al, 2011). Following the first report, transgenic mice expressing ETV6-FLT3 were used (Baldwin et al, 2007).…”

“…Acute lymphoblastic leukemia (ALL) and myeloid malignancies are described in cases of t(12;13)(p13;q12) Note The translocation t(12;13)(p13;q12) is molecularly heterogeneous: The t(12;13)(p13;q12) with ETV6 and FLT3 involvement, herein described, was found in three cases of myeloproliferative neoplasm (MPN) with eosinophilia (Vu et al, 2006;Walz et al, 2011). On the other hand, a t(12;13)(p13;q12) ETV6/CDX2 has been described in another case (Chase et al, 1999).…”