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

A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy
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 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.
bone marrow, transplantation, phosphorylation, growth, leukemia, hydroxyurea, tyrosine, atypical, lymphocyte transfusion, oncogene proteins, laboratories, methods, female, protein
0301-472X
1723-1727
Grand, Francis H.
89bd846f-638a-4bda-b8a9-8a1989021b31
Iqbal, Sameena
5466a67e-c498-4a61-8f16-7aef3c81f1c9
Zhang, Lingyan
d295dbaf-f3f8-4b19-9842-f761d41376e2
Russell, Nigel H.
c7782520-de9a-41fd-9512-2fbcd26f0401
Chase, Andrew
a40a09c2-3073-4655-ba0b-a802e34914b5
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Grand, Francis H.
89bd846f-638a-4bda-b8a9-8a1989021b31
Iqbal, Sameena
5466a67e-c498-4a61-8f16-7aef3c81f1c9
Zhang, Lingyan
d295dbaf-f3f8-4b19-9842-f761d41376e2
Russell, Nigel H.
c7782520-de9a-41fd-9512-2fbcd26f0401
Chase, Andrew
a40a09c2-3073-4655-ba0b-a802e34914b5
Cross, Nicholas C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4

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), 1723-1727. (doi:10.1016/j.exphem.2007.07.002).

Record type: Article

Abstract

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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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 Andrew Chase: ORCID iD orcid.org/0000-0001-6617-9953
ORCID for Nicholas C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 04 Sep 2008
Last modified: 16 Mar 2024 03:23

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Contributors

Author: Francis H. Grand
Author: Sameena Iqbal
Author: Lingyan Zhang
Author: Nigel H. Russell
Author: Andrew Chase ORCID iD

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