Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32)

Blood. 2005 Jun 15;105(12):4849-52. doi: 10.1182/blood-2004-12-4897. Epub 2005 Feb 15.

Abstract

The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Base Sequence
  • Benzamides
  • Blotting, Western
  • Cell Line
  • Cell Survival
  • Chromosomes, Human, Pair 14*
  • Chromosomes, Human, Pair 9*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / metabolism
  • Female
  • Fusion Proteins, bcr-abl / chemistry*
  • Gene Deletion
  • Genes, abl
  • Humans
  • Imatinib Mesylate
  • In Situ Hybridization, Fluorescence
  • Karyotyping
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, T-Cell / pathology*
  • Microtubules / metabolism
  • Milk Proteins / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Genetic
  • Molecular Sequence Data
  • Oncogene Proteins, Fusion / genetics*
  • Open Reading Frames
  • Phenotype
  • Phosphorylation
  • Piperazines / pharmacology
  • Polymerase Chain Reaction
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / pharmacology
  • Recombinant Fusion Proteins / metabolism
  • Retroviridae
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT5 Transcription Factor
  • Signal Transduction
  • Time Factors
  • Trans-Activators / metabolism
  • Translocation, Genetic*

Substances

  • Benzamides
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Complementary
  • DNA-Binding Proteins
  • EML1-ABL1 fusion protein, human
  • Milk Proteins
  • Oncogene Proteins, Fusion
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Recombinant Fusion Proteins
  • STAT5 Transcription Factor
  • Trans-Activators
  • abl-bcr fusion protein, human
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3