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

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
• Journal: Experimental hematology (Exp Hematol) Vol. 35 Issue 11 Pg. 1723-7 (Nov 2007) ISSN: 0301-472X [Print] Netherlands
• PMID: 17764812 (Publication Type: Case Reports, Journal Article)

Chemical References

• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• SPTBN1 protein, human
• Spectrin
• fms-Like Tyrosine Kinase 3
• Hydroxyurea

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)