Original Paper

Cell Death and Differentiation (2016) 23, 242–252; doi:10.1038/cdd.2015.87; published online 3 July 2015

MAP3K11 is a tumor suppressor targeted by the oncomiR miR-125b in early B cells

U Knackmuss1,4,5, S E Lindner2,5, T Aneichyk3, B Kotkamp1, Z Knust1, A Villunger2 and S Herzog1,2

  1. 1Centre for Biological Signalling Studies (bioss), Albert-Ludwigs-University Freiburg, Freiburg, Germany
  2. 2Division of Developmental Immunology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
  3. 3Division of Molecular Pathophysiology, Biocenter Innsbruck, Medical University of Innsbruck, Innsbruck, Austria

Correspondence: S Herzog, Division of Developmental Immunology, Biocenter Innsbruck, Medical University of Innsbruck, Innrain 80, Innsbruck, Tirol 6020 Austria. Tel: +43 512 9003 70381; Fax: +43 512 9003 73960; E-mail: Sebastian.herzog@i-med.ac.at

4Current address: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.

5These authors contributed equally to this work.

Received 20 November 2014; Revised 5 May 2015; Accepted 22 May 2015
Advance online publication 3 July 2015

Edited by G Melino

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Abstract

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that posttranscriptionally regulate gene expression and thereby control most, if not all, biological processes. Aberrant miRNA expression has been linked to a variety of human diseases including cancer, but the underlying molecular mechanism often remains unclear. Here we have screened a miRNA expression library in a growth factor-dependent mouse pre-B-cell system to identify miRNAs with oncogenic activity. We show that miR-125b is sufficient to render pre-B cells growth factor independent and demonstrate that continuous expression of miR-125b is necessary to keep these cells in a transformed state. Mechanistically, we find that the expression of miR-125b protects against apoptosis induced by growth factor withdrawal, and that it blocks the differentiation of pre-B to immature B cells. In consequence, miR-125b-transformed cells maintain expression of their pre-B-cell receptor that provides signals for continuous proliferation and survival even in the absence of growth factor. Employing microarray analysis, we identified numerous targets of miR-125b, but only reconstitution of MAP3K11, a critical regulator of mitogen- and stress-activated kinase signaling, interferes with the cellular fitness of the transformed cells. Together, this indicates that MAP3K11 might function as an important tumor suppressor neutralized by oncomiR-125b in B-cell leukemia.

Abbreviations:

Abtb1, ankyrin repeat and BTB (POZ) domain containing 1; ALL, acute lymphoblastic leukemia; Arid3a, AT-rich interactive domain-containing protein 3A; Bak1, BCL2-antagonist/killer 1; Bbc3, BCL2 binding component 3; BCR, B-cell receptor; Blzf1, basic leucine zipper nuclear factor 1; Bmf, Bcl2-modifying factor; BTK, Bruton's tyrosine kinase; CBFB, core-binding factor, β-subunit; EdU, ethynyl-2'-deoxyuridine; Erk, extracellular signal-regulated kinase; GFP, green fluorescent protein; HC, heavy chain; Homez, homeobox and leucine zipper encoding; IL-7, interleukin-7; Irf4, interferon regulatory factor 4; Jnk, c-Jun N-terminal kinase; KD, kinase dead; Lactb, lactamase, β; LAT, linker for activation of T cells; Mdm2, mouse double-minute 2 homolog; MFI, mean fluorescence intensity; miRNA, microRNA; PEI, polyethylenimine; Rag1, recombination activating gene 1; rtTA, tetracycline-regulated reverse transactivator; shRNA, small hairpin RNA; SLP-65, Src homology domain-containing leukocyte protein of 65 kDa; SYK, spleen tyrosine kinase; TNFAIP3, tumor necrosis factor-α-induced protein 3; Trp53inp1, transformation related protein 53 inducible nuclear protein 1; UTR, untranslated region; Rps6ka1, ribosomal protein S6 kinase 1; Sirt7, sirtuin 7; Tmem123, transmembrane protein 123