The Signaling Axis Atypical Protein Kinase C λ/ι-Satb2 Mediates Leukemic Transformation of B-cell Progenitors

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jan 6

PMID 30610188

Citations 19

Authors

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

Affiliations

Soon will be listed here.

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.

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