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

Record type: Article

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, ?, 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.

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Citation

Grand, Francis H., Iqbal, Sameena, Zhang, Lingyan, Russell, Nigel H., Chase, Andrew and Cross, Nicholas C.P. (2007) A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy Experimental Hematology, 35, (11), pp. 1723-1727. (doi:10.1016/j.exphem.2007.07.002).

More information

Published date: November 2007
Keywords: bone marrow, transplantation, phosphorylation, growth, leukemia, hydroxyurea, tyrosine, atypical, lymphocyte transfusion, oncogene proteins, laboratories, methods, female, protein

Identifiers

Local EPrints ID: 59785
URI: http://eprints.soton.ac.uk/id/eprint/59785
ISSN: 0301-472X
PURE UUID: bded4d54-3e82-453c-9deb-25e23e7de2b6
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

Catalogue record

Date deposited: 04 Sep 2008
Last modified: 17 Jul 2017 14:24

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