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Expansion of BCR / ABL 1 + cells requires PAK 2 but not PAK 1
Author(s) -
Edlinger Leo,
BergerBecvar Angelika,
Menzl Ingeborg,
Hoermann Gregor,
Greiner Georg,
Grundschober Eva,
BagoHorvath Zsuzsanna,
AlZoughbi Wael,
Hoefler Gerald,
Brostjan Christine,
Gille Lars,
Moriggl Richard,
Spittler Andreas,
Sexl Veronika,
HoelblKovacic Andrea
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14833
Subject(s) - haematopoiesis , microbiology and biotechnology , microvesicles , gene isoform , cell growth , cell culture , exosome , motility , biology , chemistry , cancer research , stem cell , biochemistry , microrna , genetics , gene
Summary The p21‐activated kinases ( PAK 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, PAK deregulation has mainly been studied in solid tumours, where PAK 1 and PAK 4 are the main isoforms deregulated. We show that PAK 1 and PAK 2 are the critical isoforms in a BCR / ABL 1 + haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK 1 and PAK 2 undergo apoptosis, while the loss of either protein is well tolerated. Transfer of medium conditioned by sh PAK 2‐ but not sh PAK 1‐expressing leukaemic cells interferes with endothelial cell growth. We found that leukaemic cells produce exosomes containing PAK 2. Transfer of isolated exosomes supports endothelial cell proliferation. In parallel, we found that leukaemic cells explicitly require PAK 2 to grow towards an extracellular matrix. PAK 2‐deficient cells fail to form colonies in methylcellulose and to induce lymphomas in vivo . PAK 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 PAK 2 isoform represents a promising target for the treatment of haematological diseases.