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

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 and J. A. Cancelas ()
Additional contact information
R. C. Nayak: Cincinnati Children’s Hospital Medical Center
S. Hegde: Cincinnati Children’s Hospital Medical Center
M. J. Althoff: Cincinnati Children’s Hospital Medical Center
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

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07846-y

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