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Edlinger, Leo; Berger‐Becvar, Angelika; Menzl, Ingeborg; Hoermann, Gregor; Greiner, Georg; Grundschober, Eva; Bago‐Horvath, Zsuzsanna; Al‐Zoughbi, Wael; Hoefler, Gerald; Brostjan, Christine; Gille, Lars; Moriggl, Richard; Spittler, Andreas; Sexl, Veronika; Hoelbl‐Kovacic, Andrea

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1

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  • Media type: E-Article
  • Title: Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1
  • Contributor: Edlinger, Leo; Berger‐Becvar, Angelika; Menzl, Ingeborg; Hoermann, Gregor; Greiner, Georg; Grundschober, Eva; Bago‐Horvath, Zsuzsanna; Al‐Zoughbi, Wael; Hoefler, Gerald; Brostjan, Christine; Gille, Lars; Moriggl, Richard; Spittler, Andreas; Sexl, Veronika; Hoelbl‐Kovacic, Andrea
  • imprint: Wiley, 2017
  • Published in: British Journal of Haematology
  • Language: English
  • DOI: 10.1111/bjh.14833
  • ISSN: 0007-1048; 1365-2141
  • Origination:
  • Footnote:
  • Description: <jats:title>Summary</jats:title><jats:p>The p21‐activated kinases (<jats:styled-content style="fixed-case">PAK</jats:styled-content>s) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, <jats:styled-content style="fixed-case">PAK</jats:styled-content> deregulation has mainly been studied in solid tumours, where <jats:styled-content style="fixed-case">PAK</jats:styled-content>1 and <jats:styled-content style="fixed-case">PAK</jats:styled-content>4 are the main isoforms deregulated. We show that <jats:styled-content style="fixed-case">PAK</jats:styled-content>1 and <jats:styled-content style="fixed-case">PAK</jats:styled-content>2 are the critical isoforms in a <jats:italic><jats:styled-content style="fixed-case">BCR</jats:styled-content>/<jats:styled-content style="fixed-case">ABL</jats:styled-content>1</jats:italic><jats:sup>+</jats:sup> haematopoietic malignancy. In suspension, leukaemic cells deficient for <jats:styled-content style="fixed-case">PAK</jats:styled-content>1 and <jats:styled-content style="fixed-case">PAK</jats:styled-content>2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by sh<jats:styled-content style="fixed-case">PAK</jats:styled-content>2‐ but not sh<jats:styled-content style="fixed-case">PAK</jats:styled-content>1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing <jats:styled-content style="fixed-case">PAK</jats:styled-content>2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require <jats:styled-content style="fixed-case">PAK</jats:styled-content>2 to grow towards an extracellular matrix. <jats:styled-content style="fixed-case">PAK</jats:styled-content>2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas <jats:italic>in vivo</jats:italic>. <jats:styled-content style="fixed-case">PAK</jats:styled-content>2 might therefore be the critical isoform in leukaemic cells by controlling tumour growth in a dual manner: vascularization via exosome‐mediated transfer to endothelial cells and remodelling of the extracellular matrix. This finding suggests that the <jats:styled-content style="fixed-case">PAK</jats:styled-content>2 isoform represents a promising target for the treatment of haematological diseases.</jats:p>