Cytoskeletal regulatory gene expression and migratory properties of B-cell progenitors are affected by the ETV6-RUNX1 rearrangement.

Chiara Palmi,Antonello Villa,Grazia Fazio,Ilaria Brunati,Angela M Savino,Pamela Della Mina,Anthony Ford,Mel Greaves,Giovanni Cazzaniga,Margherita Vieri,Giovanna D'Amico,Giulia Longinotti,Valentina Andrè,Valeria Cazzaniga,Julia Procter,Louise Howell,Andrea Biondi

doi:10.1158/1541-7786.mcr-14-0056-t

Abstract

Although the ETV6-RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent preleukemic B-cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6-RUNX1-positive cells during this "latency" period may explain how these silent cells can persist and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were used to investigate whether ETV6-RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6-RUNX1-expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK phosphorylation. Moreover, the induction of ETV6-RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6-RUNX1 preleukemic BCP with the microenvironment and contribute to the pathogenesis of the disease. Alterations in the expression of cytoskeletal regulatory genes and migration properties of BCP represent early events in the evolution of the disease, from the preleukemic phase to the clinical onset, and suggest new strategies for effective eradication of leukemia.

Highlights

ETV6–RUNX1, generated by the t(12;21) chromosome translocation, is the most common fusion gene in childhood cancer, selectively associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL; refs. 1–3)
After ETV6–RUNX1 expression in Ba/F3 cells, flow cytometric analysis indicated alterations of the cell-surface expression levels of several molecules involved in cell adhesion and migration of B-cell progenitors (BCP) [31]
ETV6–RUNX1– positive cells expressed higher levels (MFI ratio) of the following adhesion molecules: CD44, CD18, CD11a, and CD54

Summary

Introduction

ETV6–RUNX1, generated by the t(12;21) chromosome translocation, is the most common fusion gene in childhood cancer, selectively associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL; refs. 1–3). ETV6–RUNX1, generated by the t(12;21) chromosome translocation, is the most common fusion gene in childhood cancer, selectively associated with B-cell precursor acute lymphoblastic leukemia The t [12;21] translocation fuses the protein dimerization domain of ETV6 with essentially all of the DNA binding and activating regions of RUNX1, generating an aberrant transcription factor [2, 4]. Observations on clinical samples, Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). ETV6–RUNX1 fusion generated during fetal hemopoiesis produces a clinically covert preleukemic clone that can persist postnatally for at least 15 years [4]. Additional genetic abnormalities observed at diagnosis of ETV6–RUNX1–positive ALL are generally considered to be secondary events associated with the transition of silent preleukemic cells to overt ALL [4]

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