| 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, beta, 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. |
| Authors | Francis H Grand, Sameena Iqbal, Lingyan Zhang, Nigel H Russell, Andrew Chase, Nicholas C P Cross
(Affiliation: Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK. F.H.Grand at soton.ac.uk)
|
| Journal | Experimental hematology
(Exp Hematol)
Vol. 35
Issue 11
Pg. 1723-7
(Nov 2007)
ISSN: 0301-472X Netherlands |
| PMID | 17764812
(Publication Type: Case Reports, Journal Article)
|
| Chemical References |
- Oncogene Proteins, Fusion
- Protein Kinase Inhibitors
- SPTBN1 protein, human
- Spectrin
- Hydroxyurea
- fms-Like Tyrosine Kinase 3
|
| Topics |
- Adult
- Bone Marrow Transplantation
- Female
- Humans
- Hydroxyurea
(therapeutic use)
- Immunotherapy
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
(genetics, therapy)
- Lymphocyte Transfusion
- Oncogene Proteins, Fusion
(analysis, genetics)
- Protein Kinase Inhibitors
- Spectrin
(genetics)
- Translocation, Genetic
- Treatment Outcome
- fms-Like Tyrosine Kinase 3
(genetics)
|
