ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35) Journal Article

Authors: Colleoni, G. W. B.; Bridge, J. A.; Garicochea, B.; Liu, J.; Filippa, D. A.; Ladanyi, M.
Article Title: ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35)
Abstract: The subset of CD30-positive anaplastic large cell lymphomas (ALCL) with the NPM-ALK gene fusion arising from the t(2;5)(p23;q35) forms a distinct clinical and prognostic entity. Recently, various cytogenetic, molecular, and protein studies have provided evidence for the existence of several types of variant ALK fusions in up to 20% of ALK+ ALCL, of which only one, a TPM3-ALK fusion resulting from a t(1;2)(q25;p23), has so far been cloned. A cryptic inv(2)(p23q35) has been described as another recurrent cytogenetic alteration involving ALK and an unidentified fusion partner in some ALCL. In a screen for variant ALK gene fusions, we identified two ALCL that were negative for NPM-ALK by reverse transcriptase-polymerase chain reaction, but were positive for cytoplasmic ALK with both polyclonal and monoclonal antibodies to the ALK tyrosine kinase domain, consistent with ALK deregulation by an alteration other than the t(2;5) Case 1 was a T-lineage nodal and cutaneous ALCL in a 52-year-old woman, and Case 2 was a T-lineage nodal ALCL in a 12-year-old girl. FISH analysis confirmed ALK rearrangement in both cases verse polymerase chain reaction approach was then used to identify the ALK translocation partner in Case 1. We found an in-frame fusion of ALK to ATIC, a gene previously mapped to 2q34-q35. We then confirmed by DNA polymerase chain reaction the localization of ATIC to yeast artificial chromosome (YAC) 914E7 previously reported to span the 2q35 break in the inv(2)(p23q35). FISH analysis in Case 1 confirmed rearrangement of YAC 914E7 and fusion to ALK. The ATIC-ALK fusion was confirmed in Case 1 and also identified in Case 2 by conventional reverse transcriptase-polymerase chain reaction using ATIC forward and ALK reverse primers. ATIC encodes an enzyme involved in purine biosynthesis which, like other fusion partners of ALK, is constitutively expressed and appears to contain a dimerization domain. ATIC-ALK fusion resulting from the inv(2)(p23q35) thus provides a third mechanism of ALK activation in ALK+ ALCL.
Keywords: immunohistochemistry; adult; child; school child; middle aged; gene translocation; case report; in situ hybridization, fluorescence; gene expression; genetic variability; protein tyrosine kinase; chromosomes, human, pair 2; cloning, molecular; gene mapping; gene activation; gene rearrangement; reverse transcriptase polymerase chain reaction; dna, neoplasm; gene fusion; oncogene proteins, fusion; gene control; protein-tyrosine kinases; large cell lymphoma; dna primers; multienzyme complexes; chromosome inversion; inversion, chromosome; lymphoma, large-cell, ki-1; humans; prognosis; human; female; priority journal; article; hydroxymethyl and formyl transferases; nucleotide deaminases
Journal Title: American Journal of Pathology
Volume: 156
Issue: 3
ISSN: 0002-9440
Publisher: Elsevier Science, Inc.  
Date Published: 2000-03-01
Start Page: 781
End Page: 789
Language: English
PUBMED: 10702393
PROVIDER: scopus
PMCID: PMC1876849
DOI: 10.1016/S0002-9440(10)64945-0
Notes: Export Date: 18 November 2015 -- Source: Scopus
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MSK Authors
  1. Marc Ladanyi
    885 Ladanyi
  2. Daniel A Filippa
    103 Filippa