A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia

N Engl J Med. 2005 Oct 27;353(17):1793-801. doi: 10.1056/NEJMoa050995.


Background: MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL.

Methods: We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgV(H) ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities.

Results: A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgV(H) from those with mutated IgV(H) . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germ-line or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (P<0.001).

Conclusions: A unique microRNA signature is associated with prognostic factors and disease progression in CLL. Mutations in microRNA transcripts are common and may have functional importance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Disease Progression
  • Female
  • Gene Expression Profiling
  • Gene Expression*
  • Gene Rearrangement
  • Genes, Immunoglobulin
  • Genes, Tumor Suppressor
  • Germ-Line Mutation
  • Humans
  • Immunoglobulin Heavy Chains / genetics*
  • Immunoglobulin Heavy Chains / metabolism
  • Immunoglobulin Variable Region / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Male
  • MicroRNAs* / analysis
  • MicroRNAs* / metabolism
  • Mutation*
  • Oligonucleotide Array Sequence Analysis
  • Point Mutation
  • Prognosis
  • Protein-Tyrosine Kinases / metabolism*
  • Sequence Analysis, DNA
  • ZAP-70 Protein-Tyrosine Kinase


  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • MicroRNAs
  • Protein-Tyrosine Kinases
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human