title: ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions.
abstract: We report 2 ALK-positive large B-cell lymphoma cases showing granular cytoplasmic and cytoplasmic/nuclear ALK immunostaining in which cryptic ALK rearrangements were identified by fluorescent in situ hybridization and molecular analysis. In the first case, the ALK-involving t(2;3)(p23;q27) masked the cryptic SEC31A-ALK fusion generated by an insertion of the 5' end of SEC31A (4q21) upstream of the 3' end of ALK. This rearrangement was associated with loss of the 5' end of ALK and duplication of SEC31A-ALK on der(20). In the second case with complex rearrangements of both chromosomes 2, a submicroscopic NPM1-ALK fusion created by insertion of the 3' end of ALK into the NPM1 locus was evidenced. Further studies of SEC31A-ALK showed that this variant fusion transforms IL3-dependent Ba/F3 cells to growth factor independence, and that the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3 and STAT5.
authors.affiliation: Center for Human Genetics, K.U. Leuven, Gasthuisberg, Herestraat 49, Box 602, B-3000 Leuven, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Roosbroeck
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Daan
authors.initials: D
authors.lastname: Dierickx
authors.forename: José
authors.initials: J
authors.lastname: Thomas
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Michel
authors.initials: M
authors.lastname: Stul
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Chris
authors.initials: C
authors.lastname: De Wolf-Peeters
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D002877:Chromosomes, Human / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C000716967:NPM1 protein, human; D015514:Oncogene Proteins, Fusion; C507455:SEC31A protein, human; D033921:Vesicular Transport Proteins; D000090243:Nucleophosmin; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases