The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation.
Anaplastic large cell lymphoma (ALCL) is a non-Hodgkin's lymphoma that originates from T cells and frequently expresses oncogenic fusion proteins derived from chromosomal translocations or inversions of the anaplastic lymphoma kinase (ALK) gene. The proliferation and survival of ALCL cells are determined by the ALK activity. Here we show that the kinase activity of the nucleophosmin (NPM)-ALK fusion regulated the shape of ALCL cells and F-actin filament assembly in a pattern similar to T-cell receptor-stimulated cells. NPM-ALK formed a complex with the guanine exchange factor VAV1, enhancing its activation through phosphorylation. VAV1 increased Cdc42 activity, and in turn, Cdc42 regulated the shape and migration of ALCL cells. In vitro knockdown of VAV1 or Cdc42 by short hairpin RNA, as well as pharmacologic inhibition of Cdc42 activity by secramine, resulted in a cell cycle arrest and apoptosis of ALCL cells. Importantly, the concomitant inhibition of Cdc42 and NPM-ALK kinase acted synergistically to induce apoptosis of ALCL cells. Finally, Cdc42 was necessary for the growth as well as for the maintenance of already established lymphomas in vivo. Thus, our data open perspectives for new therapeutic strategies by revealing a mechanism of regulation of ALCL cell growth through Cdc42.
Ambrogio
Chiara
C
Department of Biomedical Sciences and Human Oncology, Center for Experimental Research and Medical Studies, University of Torino, Turin, Italy.
Voena
Claudia
C
Manazza
Andrea D
AD
Martinengo
Cinzia
C
Costa
Carlotta
C
Kirchhausen
Tomas
T
Hirsch
Emilio
E
Inghirami
Giorgio
G
Chiarle
Roberto
R
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D048430:Cell Shape; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020764:cdc42 GTP-Binding Protein