title: Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32).
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.
authors.affiliation: Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Carlos
authors.initials: C
authors.lastname: Graux
authors.forename: Maria D
authors.initials: MD
authors.lastname: Odero
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Riet
authors.initials: R
authors.lastname: Somers
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Anne
authors.initials: A
authors.lastname: Hagemeijer
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D001549:Benzamides; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D002883:Chromosomes, Human, Pair 14; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry*; D017353:Gene Deletion; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D015458:Leukemia, T-Cell / Q000473:pathology*; D008870:Microtubules / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016366:Open Reading Frames; D010641:Phenotype; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D001549:Benzamides; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C501947:EML1-ABL1 fusion protein, human; D008894:Milk Proteins; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3