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Science 14 November 1997:
Vol. 278. no. 5341, pp. 1309 - 1312
DOI: 10.1126/science.278.5341.1309
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Reports

A TEL-JAK2 Fusion Protein with Constitutive Kinase Activity in Human Leukemia

Virginie Lacronique, Anthony Boureux, Véronique Della Valle, Hélène Poirel, Christine Tran Quang, Martine Mauchauffé, Christian Berthou, Michel Lessard, Roland Berger, Jacques Ghysdael, Olivier A. Bernard *

The Janus family of tyrosine kinases (JAK) plays an essential role in development and in coupling cytokine receptors to downstream intracellular signaling events. A t(9;12)(p24;p13) chromosomal translocation in a T cell childhood acute lymphoblastic leukemia patient was characterized and shown to fuse the 3' portion of JAK2 to the 5' region of TEL, a gene encoding a member of the ETS transcription factor family. The TEL-JAK2 fusion protein includes the catalytic domain of JAK2 and the TEL-specific oligomerization domain. TEL-induced oligomerization of TEL-JAK2 resulted in the constitutive activation of its tyrosine kinase activity and conferred cytokine-independent proliferation to the interleukin-3-dependent Ba/F3 hematopoietic cell line.

V. Lacronique, V. Della Valle, H. Poirel, M. Mauchauffé, R. Berger, O. A. Bernard, U 301 de l'Institut National de la Santé et de la Recherche Médicale and SD 401 No. 301 CNRS, Institut de Génétique Moléculaire, 27 rue Juliette Dodu, 75010 Paris, France.
A. Boureux, C. Tran Quang, J. Ghysdael, CNRS Unité Mixte de Recherche 146, Institut Curie-Section de Recherche, Centre Universitaire, 91405 Orsay Cedex, France.
C. Berthou and M. Lessard, Unité d'Hématologie, Laboratoire de Cytogénétique, Hôpital Morvan, Centre Hospitalier Régional de Brest, 29609 Brest Cedex, France.
*   To whom correspondence should be addressed.

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A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9.
A. B. Dash, I. R. Williams, J. L. Kutok, M. H. Tomasson, E. Anastasiadou, K. Lindahl, S. Li, R. A. Van Etten, J. Borrow, D. Housman, et al. (2002)
PNAS 99, 7622-7627
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Regulation of Jak2 through the Ubiquitin-Proteasome Pathway Involves Phosphorylation of Jak2 on Y1007 and Interaction with SOCS-1.
D. Ungureanu, P. Saharinen, I. Junttila, D. J. Hilton, and O. Silvennoinen (2002)
Mol. Cell. Biol. 22, 3316-3326
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Interactions of STAT5b-RARalpha , a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways.
S. Dong and D. J. Tweardy (2002)
Blood 99, 2637-2646
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Activated Fes Protein Tyrosine Kinase Induces Terminal Macrophage Differentiation of Myeloid Progenitors (U937 Cells) and Activation of the Transcription Factor PU.1.
J. Kim and R. A. Feldman (2002)
Mol. Cell. Biol. 22, 1903-1918
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Identification of Akt Association and Oligomerization Domains of the Akt Kinase Coactivator TCL1.
G. Kunstle, J. Laine, G. Pierron, S.-i. Kagami, H. Nakajima, F. Hoh, C. Roumestand, M.-H. Stern, and M. Noguchi (2002)
Mol. Cell. Biol. 22, 1513-1525
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SH2-B Family Members Differentially Regulate JAK Family Tyrosine Kinases.
K. B. O'Brien, J. J. O'Shea, and C. Carter-Su (2002)
J. Biol. Chem. 277, 8673-8681
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Differential Regulation of Akt Kinase Isoforms by the Members of the TCL1 Oncogene Family.
J. Laine, G. Kunstle, T. Obata, and M. Noguchi (2002)
J. Biol. Chem. 277, 3743-3751
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An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.
J. J. Seidel and B. J. Graves (2002)
Genes & Dev. 16, 127-137
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FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model.
L. M. Kelly, Q. Liu, J. L. Kutok, I. R. Williams, C. L. Boulton, and D. G. Gilliland (2002)
Blood 99, 310-318
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8p12 Stem Cell Myeloproliferative Disorder: the FOP-Fibroblast Growth Factor Receptor 1 Fusion Protein of the t(6;8) Translocation Induces Cell Survival Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt/mTOR Pathways.
G. Guasch, V. Ollendorff, J.-P. Borg, D. Birnbaum, and M.-J. Pebusque (2001)
Mol. Cell. Biol. 21, 8129-8142
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Fusion of ETV6 to Fibroblast Growth Factor Receptor 3 in Peripheral T-Cell Lymphoma with a t(4;12)(p16;p13) Chromosomal Translocation.
F. Yagasaki, D. Wakao, Y. Yokoyama, Y. Uchida, I. Murohashi, H. Kayano, M. Taniwaki, A. Matsuda, and M. Bessho (2001)
Cancer Res. 61, 8371-8374
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The Chimeric Protein Tyrosine Kinase ETV6-NTRK3 Requires both Ras-Erk1/2 and PI3-Kinase-Akt Signaling for Fibroblast Transformation.
C. Tognon, M. Garnett, E. Kenward, R. Kay, K. Morrison, and P. H. B. Sorensen (2001)
Cancer Res. 61, 8909-8916
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The TEL/PDGFbeta R fusion in chronic myelomonocytic leukemia signals through STAT5-dependent and STAT5-independent pathways.
D. W. Sternberg, M. H. Tomasson, M. Carroll, D. P. Curley, G. Barker, M. Caprio, A. Wilbanks, A. Kazlauskas, and D. G. Gilliland (2001)
Blood 98, 3390-3397
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Growth Factor Signaling in Cell Survival: Implications for Cancer Treatment.
S. Talapatra and C. B. Thompson (2001)
J. Pharmacol. Exp. Ther. 298, 873-878
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STAT3 is constitutively activated in Hodgkin cell lines.
D. Kube, U. Holtick, M. Vockerodt, T. Ahmadi, B. Haier, I. Behrmann, P. C. Heinrich, V. Diehl, and H. Tesch (2001)
Blood 98, 762-770
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H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor {beta} gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22).
J. Schwaller, E. Anastasiadou, D. Cain, J. Kutok, S. Wojiski, I. R. Williams, R. LaStarza, B. Crescenzi, D. W. Sternberg, P. Andreasson, et al. (2001)
Blood 97, 3910-3918
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Socs-1 Inhibits TEL-JAK2-Mediated Transformation of Hematopoietic Cells through Inhibition of JAK2 Kinase Activity and Induction of Proteasome-Mediated Degradation.
J. Frantsve, J. Schwaller, D. W. Sternberg, J. Kutok, and D. G. Gilliland (2001)
Mol. Cell. Biol. 21, 3547-3557
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Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy between AG490 and STI571.
X. Sun, J. E. Layton, A. Elefanty, and G. J. Lieschke (2001)
Blood 97, 2008-2015
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The Diverse Role of the ETS Family of Transcription Factors in Cancer: Commentary re: B. Davidson, Ets-1 Messenger RNA Expression Is a Novel Marker of Poor Survival in Ovarian Carcinoma. Clin. Cancer Res., 7: 551-557, 2001..
D. G. Gilliland (2001)
Clin. Cancer Res. 7, 451-453
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Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12).
Y. Kuno, A. Abe, N. Emi, M. Iida, T. Yokozawa, M. Towatari, M. Tanimoto, and H. Saito (2001)
Blood 97, 1050-1055
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Acute Myeloid Leukemia.
F. R. Appelbaum, J. M. Rowe, J. Radich, and J. E. Dick (2001)
Hematology 2001, 62-86
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The MN1-TEL Fusion Protein, Encoded by the Translocation (12;22)(p13;q11) in Myeloid Leukemia, Is a Transcription Factor with Transforming Activity.
A. Buijs, L. van Rompaey, A. C. Molijn, J. N. Davis, A. C. O. Vertegaal, M. D. Potter, C. Adams, S. van Baal, E. C. Zwarthoff, M. F. Roussel, et al. (2000)
Mol. Cell. Biol. 20, 9281-9293
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