Jak1 deficiency leads to enhanced Abelson-induced B-cell tumor formation.
The Janus kinase Jak1 has been implicated in tumor formation by the Abelson oncogene. In this study we show that loss of Jak1 does not affect in vitro transformation by v-abl as defined by the ability to induce cytokine-independent B-cell colony formation or establishment of B-cell lines. However, Jak1-deficient, v-abl-transformed cell lines were more tumorgenic than wild-type cells when transplanted subcutaneously into severe combined immunodeficient (SCID) mice or injected intravenously into nude mice. Jak1 deficiency was associated with a loss in the ability of interferon-gamma (IFN-gamma)to induce growth arrest and/or apoptosis of v-abl-transformed pre-B cells or tumor growth in SCID mice. Moreover, IFN-gamma mRNA could be detected in growing tumors, and tumor cells explanted from SCID mice had lost the ability to respond to IFN-gamma in 9 of 20 cases, whereas the response to interferon-alpha (IFN-alpha) remained intact. Importantly, a similar increase in tumorgenicity was observed when IFN-gamma-deficient cells were injected into SCID mice, identifying the tumor cell itself as the main source of IFN-gamma. These findings demonstrate that Jak1, rather than promoting tumorgenesis as previously proposed, is critical in mediating an intrinsic IFN-gamma-dependent tumor surveillance.
Sexl
Veronika
V
Department of Pharmacology, Vienna University, Austria. veronika.sexl@univie.ac.at
Kovacic
Boris
B
Piekorz
Roland
R
Moriggl
Richard
R
Stoiber
Dagmar
D
Hoffmeyer
Angelika
A
Liebminger
Rita
R
Kudlacek
Oliver
O
Weisz
Eva
E
Rothammer
Kristen
K
Ihle
James N
JN
D000011:Abelson murine leukemia virus; D000818:Animals; D001402:B-Lymphocytes; D002471:Cell Transformation, Neoplastic; D046508:Culture Techniques; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D053613:Janus Kinase 1; D008099:Liver / Q000196:embryology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009693:Nucleic Acid Hybridization; D016374:Oncogene Proteins v-abl / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016898:Interferon-alpha; D016374:Oncogene Proteins v-abl; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1