BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells

Oncogene. 2006 Feb 16;25(7):1118-24. doi: 10.1038/sj.onc.1209133.


Pre-B lymphoblastic leukemia cells carrying a BCR-ABL1 gene rearrangement exhibit an undifferentiated phenotype. Comparing the genome-wide gene expression profiles of normal B-cell subsets and BCR-ABL1+ pre-B lymphoblastic leukemia cells by SAGE, the leukemia cells show loss of B lymphoid identity and aberrant expression of myeloid lineage-specific molecules. Consistent with this, BCR-ABL1+ pre-B lymphoblastic leukemia cells exhibit defective expression of IKAROS, a transcription factor needed for early lymphoid lineage commitment. As shown by inducible expression of BCR-ABL1 in human and murine B-cell precursor cell lines, BCR-ABL1 induces the expression of a dominant-negative IKAROS splice variant, termed IK6. Comparing matched leukemia sample pairs from patients before and during therapy with the BCR-ABL1 kinase inhibitor STI571 (Imatinib), inhibition of BCR-ABL1 partially corrected aberrant expression of IK6 and lineage infidelity of the leukemia cells. To elucidate the contribution of IK6 to lineage infidelity in BCR-ABL1+ cell lines, IK6 expression was silenced by RNA interference. Upon inhibition of IK6, BCR-ABL1+ leukemia cells partially restored B lymphoid lineage commitment. Therefore, we propose that BCR-ABL1 induces aberrant splicing of IKAROS, which interferes with lineage identity and differentiation of pre-B lymphoblastic leukemia cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Benzamides
  • Cell Line, Tumor
  • Cell Lineage / genetics
  • Cell Nucleus / chemistry
  • Fusion Proteins, bcr-abl
  • Gene Expression Profiling
  • Gene Silencing
  • Humans
  • Ikaros Transcription Factor / analysis
  • Ikaros Transcription Factor / genetics*
  • Ikaros Transcription Factor / metabolism
  • Imatinib Mesylate
  • Mice
  • Piperazines / pharmacology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / diet therapy
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / enzymology*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / analysis
  • Protein-Tyrosine Kinases / metabolism*
  • Pyrimidines / pharmacology


  • Antineoplastic Agents
  • Benzamides
  • IKZF1 protein, human
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Ikaros Transcription Factor
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl