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Nat Commun. 2019 Jan 4;10(1):46. doi: 10.1038/s41467-018-07846-y.

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

Author information

1
Division of Experimental Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
2
Hoxworth Blood Center, University of Cincinnati, 3130 Highland Ave., Cincinnati, OH, 45267, USA.
3
Graduate Program of Cancer & Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
4
Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
5
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
6
Division of Experimental Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA. jose.cancelas@uc.edu.
7
Hoxworth Blood Center, University of Cincinnati, 3130 Highland Ave., Cincinnati, OH, 45267, USA. jose.cancelas@uc.edu.
8
Graduate Program of Cancer & Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA. jose.cancelas@uc.edu.

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.

PMID:
30610188
PMCID:
PMC6320370
DOI:
10.1038/s41467-018-07846-y
[Indexed for MEDLINE]
Free PMC Article

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