Bcl-XL down-regulation suppresses the tumorigenic potential of NPM/ALK in vitro and in vivo.
Deregulated apoptosis is a common finding in tumorigenesis. The oncogenic tyrosine kinase nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) delivers a strong survival signal in anaplastic large cell lymphomas (ALCLs). Although NPM/ALK activates multiple antiapoptotic pathways, the biologic relevance and therapeutic potential of more downstream apoptotic effectors are mostly unknown. In this report, the NPM/ALK-mediated induction of Bcl-XL (but not of Bcl-2) was identified in human ALCL-derived cells. NPM/ALK kinase activity was required to promote Bcl-XL expression and its protective effect on mitochondrial homeostasis. Down-regulation of Bcl-XL significantly reduced the antiapoptotic potential of NPM/ALK in both transformed murine Ba/F3 pro-B cells and human ALCL-derived KARPAS-299 cells. To elucidate the role of Bcl-XL in vivo, Ba/F3-NPM/ALK+ cells expressing a doxycycline (Dox)-inducible Bcl-XL antisense transgene (pTet-ON) were injected into nude mice. Doxycycline administration prevented a fatal systemic disease in 15 of 15 intravenously injected mice and the appearance of subcutaneous tumor xenografts in 9 of 12 mice; in vivo down-regulation of Bcl-XL was also documented. Our results show a pivotal role for Bcl-XL in ALK-mediated oncogenicity; a single protein placed downstream of a known oncogene can be crucial for the survival of neoplastic cells both in vitro and in vivo. Bcl-XL deserves further investigation as a possible therapeutic target in ALK+ ALCLs.
Coluccia
Addolorata Maria Luce
AM
Department of Experimental Oncology, National Cancer Institute, Milan, Italy.
Perego
Silvia
S
Cleris
Loredana
L
Gunby
Rosalind Helen
RH
Passoni
Lorena
L
Marchesi
Edoardo
E
Formelli
Franca
F
Gambacorti-Passerini
Carlo
C
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D001483:Base Sequence; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005260:Female; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D000090243:Nucleophosmin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases