Abstract
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.
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Accession codes
Abbreviations
- IGH :
-
immunoglobulin heavy chain
- SAGE:
-
serial analysis of gene expression
- siRNA:
-
short-interfering RNA
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Acknowledgements
We would like to thank Martin Krönke (Köln), Janet D Rowley (Chicago) and Klaus Rajewsky (Boston) for continuous support, Wolf-Karsten Hofmann (Berlin) for provision of leukemia samples, George Q Daley (Cambridge) for provision of TONB210, and Stefanie Jauch and Peter Wurst for excellent technical assistance. FK is supported by the Studienstiftung des deutschen Volkes and the Köln Fortune program of the Faculty of Medicine of the University of Cologne. NF is supported by a fellowship of the José-Carreras-Leukemia Foundation. MM is supported by the Deutsche Forschungsgemeinschaft through the Emmy-Noether-Programm, the German José-Carreras-Leukemia-Foundation (grant to MM), the Deutsche Krebshilfe through joint project grant ‘Mechanisms of Malignant Lymphoma’ (MM) and the Ministry of Science and Research for North Rhine-Westphalia through the Stem Cell Network NRW (to MM).
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Klein, F., Feldhahn, N., Herzog, S. et al. BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Oncogene 25, 1118–1124 (2006). https://doi.org/10.1038/sj.onc.1209133
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DOI: https://doi.org/10.1038/sj.onc.1209133
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