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The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors

Author

Listed:
  • R. C. Nayak

    (Cincinnati Children’s Hospital Medical Center)

  • S. Hegde

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati)

  • M. J. Althoff

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati
    University of Cincinnati College of Medicine)

  • A. M. Wellendorf

    (Cincinnati Children’s Hospital Medical Center)

  • F. Mohmoud

    (University of Cincinnati College of Medicine)

  • J. Perentesis

    (Cincinnati Children’s Hospital Medical Center)

  • M. Reina-Campos

    (Sanford Burnham Prebys Medical Discovery Institute)

  • D. Reynaud

    (Cincinnati Children’s Hospital Medical Center)

  • Y. Zheng

    (Cincinnati Children’s Hospital Medical Center)

  • M. T. Diaz-Meco

    (Sanford Burnham Prebys Medical Discovery Institute)

  • J. Moscat

    (Sanford Burnham Prebys Medical Discovery Institute)

  • J. A. Cancelas

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati
    University of Cincinnati College of Medicine)

Abstract

Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage leukemogenesis. Primary human and murine BCR-ABL+ leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCζ behaves as a leukemic suppressor, aPKCλ/ι is critically required for oncogenic progenitor proliferation, survival, and B-cell differentiation arrest, but not for normal B-cell lineage differentiation. In vitro and in vivo B-cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKC λ/ι-Erk dependent Etv5/Satb2 chromatin repressive signaling complex. Genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. Therefore, the aPKCλ/ι-SATB2 signaling cascade is required for leukemic BCR-ABL+ B-cell progenitor transformation and is amenable to non-tyrosine kinase inhibition.

Suggested Citation

  • R. C. Nayak & S. Hegde & M. J. Althoff & A. M. Wellendorf & F. Mohmoud & J. Perentesis & M. Reina-Campos & D. Reynaud & Y. Zheng & M. T. Diaz-Meco & J. Moscat & J. A. Cancelas, 2019. "The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07846-y
    DOI: 10.1038/s41467-018-07846-y
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