Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts

Blood. 2016 Jan 14;127(2):221-32. doi: 10.1182/blood-2014-12-614503. Epub 2015 Oct 13.


Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 5' RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 5' untranslated regions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Anaplastic Lymphoma Kinase
  • Animals
  • Codon, Nonsense
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / classification
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • NIH 3T3 Cells
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, ErbB-4 / genetics*
  • Receptor, ErbB-4 / metabolism


  • 5' Untranslated Regions
  • Codon, Nonsense
  • Mutant Proteins
  • RNA, Messenger
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • ERBB4 protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor, ErbB-4

Associated data

  • GENBANK/KT281867
  • GENBANK/KT310076