Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia

Leonie Smeenk, Maria Fischer, Sabine Jurado, Markus Jaritz, Anna Azaryan, Barbara Werner, Mareike Roth, Johannes Zuber, Martin Stanulla, Monique L den Boer, Charles G Mullighan, Sabine Strehl, Meinrad Busslinger

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here, we studied the function of PAX5-ETV6 and PAX5-FOXP1 in mice expressing these proteins from the Pax5 locus. Both proteins arrested B-lymphopoiesis at the pro-B to pre-B-cell transition and, contrary to their proposed dominant-negative role, did not interfere with the expression of most regulated Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressors in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-B-cell receptor (BCR) signaling and migration/adhesion, which could contribute to the proliferation, survival, and tissue infiltration of leukemic B cells. Together with similar observations made in human PAX5-ETV6+ B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein that drives B-cell leukemia development.

Original languageEnglish
Pages (from-to)718-735
Number of pages18
JournalThe EMBO journal
Volume36
Issue number6
DOIs
Publication statusPublished - 15 Mar 2017
Externally publishedYes

Keywords

  • Animals
  • Forkhead Transcription Factors/genetics
  • Mice
  • Oncogene Proteins/genetics
  • PAX5 Transcription Factor/genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology
  • Proto-Oncogene Proteins c-ets/genetics
  • Recombinant Fusion Proteins/genetics
  • Repressor Proteins/genetics

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