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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2076-2083
Transforming properties of chimeric TEL-JAK proteins in Ba/F3
cells
Virginie Lacronique,
Anthony Boureux,
Richard Monni,
Stephanie Dumon,
Martine Mauchauffé,
Patrick Mayeux,
Fabrice Gouilleux,
Roland Berger,
Sylvie Gisselbrecht,
Jacques Ghysdael, and
Olivier A. Bernard
From U434 INSERM, Centre d'Etude du Polymorphisme Humain (CEPH),
Paris, France; UMR 146 CNRS, Institut Curie-Section
Recherche, Centre Universitaire, Orsay, France; U363
INSERM, Institut Cochin de Génétique Moléculaire
(ICGM), Université René Descartes, Paris, France.
The involvement of the cytokine signaling pathway in oncogenesis has
long been postulated. Recently, rearrangements of the gene encoding the
tyrosine Janus kinase 2 (JAK2) have been reported in human leukemias
indicating a direct JAK-signal transduction and activator of
transcription (STAT)-mediated leukemic process. The leukemia-associated
TEL-JAK2 fusion protein is formed by the oligomerization domain of the
translocated ets leukemia (TEL) protein fused to the catalytic domain
of JAK2. TEL-mediated oligomerization results in a constitutive
tyrosine kinase activity that, in turn, is able to confer growth factor
independence to the murine hematopoietic interleukin-3 (IL-3)-dependent
Ba/F3 cell line. Results of the present study indicate that fusion
proteins containing the oligomerization domain of TEL and the tyrosine
kinase domains of Jak1, Jak2, JAK3, or TYK2 share similar properties
and are able to efficiently substitute for the survival and mitogenic
signals controlled by IL-3, without concomitant activation of the IL-3
receptor. Electrophoretic mobility shift assays demonstrated Stat5 as
the only activated Stat factor in TEL-Jak2- and TEL-Jak1-expressing
cells, whereas other Stats, namely Stat1 and Stat3, could be detected
in TEL-JAK3-, TEL-TYK2-, and also in TEL-ABL-expressing Ba/F3 cells.
High levels of expression of the Stat5-target genes pim-1, osm, and Cis
were observed in all the cytokine-independent cell lines. Furthermore,
the expression of a dominant negative form of Stat5A markedly
interfered with the growth factor independence process mediated by
TEL-Jak2 in Ba/F3 cells. Because the BCR-ABL and TEL-PDGF R
oncoproteins also activate Stat5, activation of this factor should be a
crucial step in activated tyrosine kinase-mediated leukemogenesis.
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