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A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy

Objectives To determine the consequences and significance of an acquired 46XX,t(2;13;2;21)(p13;q12;q33;q11.2) in atypical chronic myeloid leukemia (aCML). Methods Translocation breakpoints were identified by fluorescence in situ hybridization and a novel fusion gene identified by rapid amplification...

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Published in:Experimental hematology 2007-11, Vol.35 (11), p.1723-1727
Main Authors: Grand, Francis H, Iqbal, Sameena, Zhang, Lingyan, Russell, Nigel H, Chase, Andrew, Cross, Nicholas C.P
Format: Article
Language:English
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Summary:Objectives To determine the consequences and significance of an acquired 46XX,t(2;13;2;21)(p13;q12;q33;q11.2) in atypical chronic myeloid leukemia (aCML). Methods Translocation breakpoints were identified by fluorescence in situ hybridization and a novel fusion gene identified by rapid amplification of cDNA ends polymerase chain reaction. Functional analysis of the fusion was performed using the Ba/F3 transformation assay and specific inhibition demonstrated using small molecule inhibitors. Results Fluorescence in situ hybridization indicated that FLT3 at 13q12 was disrupted and 5′-rapid amplification of cDNA ends polymerase chain reaction identified a novel in-frame mRNA fusion between exon 3 of SPTBN1 (spectrin, β, nonerythrocytic 1) at chromosome 2p16 and exon 13 of FLT3 . Expression of SPTBN1-FLT3 transformed Ba/F3 cells to growth factor independence and was accompanied by constitutive phosphorylation of the fusion protein and the downstream substrate extracellular signal-regulated kinase 1/2. The growth of transformed cells was inhibited in a dose-dependent fashion by SU11657, PKC412, and TKI258 (CHIR-258), but not by imatinib. To determine if FLT3 might be involved more widely in BCR-ABL –negative aCML, we analyzed 40 cases and found two were internal tandem duplication–positive, but D835 mutations were not observed. The t(2;13;2;21) patient was initially treated with hydroxyurea and subsequently underwent an unrelated donor bone marrow transplantation. She relapsed cytogenetically at 4 years, but responded to donor lymphocyte infusion, achieving sustained cytogenetic and molecular (nested reverse transcription polymerase chain reaction) remission. Conclusion Although FLT3 abnormalities are uncommon in aCML, SPTBN1-FLT3 is a novel constitutively active tyrosine kinase that appears to responsive to both targeted signal transduction therapy and immunotherapy.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2007.07.002