The signaling axis atypical protein kinase C \u03bb/\u03b9-Satb2 mediates leukemic transformation of B-cell progenitors

R C Nayak,F Mohmoud,D Reynaud,S Hegde,Y Zheng,J A Cancelas,J Perentesis,M J Althoff,J Moscat,M T Diaz-Meco,M Reina-Campos,A M Wellendorf

doi:10.1038/s41467-018-07846-y

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.

Highlights

Regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy
Leukemic B-cell progenitors derived from BCR-ABL+ B-cell acute lymphoblastic leukemia (B-ALL) patients showed enhanced atypical protein kinase Cι (aPKCι) expression in comparison to healthy donor bone marrow (BM) derived B-cell progenitors (Supplementary Figure 1D)
B-cell progenitors from both healthy donors and B-ALL patients express very reduced levels of Atypical protein kinase Cζ (aPKCζ) compared with aPKCι (Supplementary Figure 1E)

Summary

Introduction

Regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL expression, genetic instability, increased proliferation, reduced apoptosis, and a blockade of differentiation where myeloid or lymphoid progenitors/precursors fail to differentiate, resulting in the development of acute myelogenous leukemia (AML) or B-cell acute lymphoblastic leukemia (B-ALL)[2,3,4,5]. Atypical protein kinase Cζ (aPKCζ) and -λ/ι (aPKCλ, mouse homolog; aPKCι, human homolog) are the sole kinases in the apical polarity complex Both aPKCs can interact with PAR6 through their respective PB1 domains, and together with PAR3 form the apical polarity complex that activate and segregate the downstream effector Numb, and dictate the asymmetric cell division of stem cells and progenitors during embryonic development and adult tissue homeostasis[12,17]

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Conclusion