title: A constitutively active SPTBN1-FLT3 fusion in atypical chronic myeloid leukemia is sensitive to tyrosine kinase inhibitors and immunotherapy.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK. F.H.Grand@soton.ac.uk
authors.forename: Francis H
authors.initials: FH
authors.lastname: Grand
authors.forename: Sameena
authors.initials: S
authors.lastname: Iqbal
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Russell
authors.forename: Andrew
authors.initials: A
authors.lastname: Chase
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D000328:Adult; D016026:Bone Marrow Transplantation; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D007167:Immunotherapy; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000235:genetics* / Q000628:therapy*; D017710:Lymphocyte Transfusion; D015514:Oncogene Proteins, Fusion / Q000032:analysis* / Q000235:genetics; D047428:Protein Kinase Inhibitors; D013049:Spectrin / Q000235:genetics*; D014178:Translocation, Genetic; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C452439:SPTBN1 protein, human; D013049:Spectrin; D051941:fms-Like Tyrosine Kinase 3; D006918:Hydroxyurea