Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death.
The anaplastic lymphoma kinase (ALK) gene is characteristically translocated in Anaplastic Large Cell Lymphomas (ALCL) and the juxtaposition of the ALK gene to multiple partners results in its constitutive protein tyrosine kinase activity. We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs. Furthermore, immunohistochemical studies demonstrate that among distinct human B and T cell lymphomas, activation of Stat3 nuclear translocation is uniquely associated with ALK expression. NPM-ALK also binds and activates Jak3; however, Jak3 is not required for Stat3 activation or for cell transformation in vitro. Moreover, src family kinases are not necessary for NPM-ALK-mediated Stat3 activation or transformation, suggesting that Stat3 may be phosphorylated directly by ALK. To evaluate relevant targets of ALK-activated Stat3, we investigated the regulation of the anti-apoptotic protein Bcl-x(L) and its role in cell survival in NPM-ALK positive cells. NPM-ALK expression caused enhanced Bcl-x(L) transcription, largely mediated by Stat3. Increased expression of Bcl-x(L) provided sufficient anti-apoptotic signals to protect cells from treatment with specific inhibitors of the Jaks/Stat pathway or the Brc-Abl kinase. These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells.
Zamo
Alberto
A
Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Chiarle
Roberto
R
Piva
Roberto
R
Howes
Jennifer
J
Fan
Yan
Y
Chilosi
Marco
M
Levy
David E
DE
Inghirami
Giorgio
G
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053616:Janus Kinase 3; D017728:Lymphoma, Large-Cell, Anaplastic / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D051020:bcl-X Protein; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D016392:Proto-Oncogene Proteins pp60(c-src)