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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1435-1441
NEOPLASIA
Induction of myeloproliferative disease in mice by tyrosine
kinase fusion oncogenes does not require granulocyte-macrophage
colony-stimulating factor or interleukin-3
Michael H. Tomasson,
Ifor
R. Williams,
Shaoguang Li,
Jeffrey Kutok,
Danielle Cain,
Silke Gillessen,
Glenn Dranoff,
Richard A. Van
Etten, and
D. Gary Gilliland
From the Division of Hematology, Department of
Medicine, Department of Pathology, Brigham and Women's Hospital,
Harvard Institutes of Medicine, Center for Blood Research, Department
of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical
School, Boston MA; Department of Pathology, Emory University School of
Medicine, Atlanta, GA; and the Howard Hughes Medical Institute, Boston,
MA.
Tyrosine kinase fusion oncogenes that occur as a result of
chromosomal translocations have been shown to activate proliferative and antiapoptotic pathways in leukemic cells, but the importance of
autocrine and paracrine expression of hematopoietic cytokines in
leukemia pathogenesis is not understood. Evidence that leukemic transformation may be, at least in part, cytokine dependent includes data from primary human leukemia cells, cell culture experiments, and
murine models of leukemia. This report demonstrates that interleukin (IL)-3 plasma levels are elevated in myeloproliferative disease (MPD)
caused by the TEL/tyrosine kinase fusions TEL/platelet-derived growth
factor beta receptor (PDGF R), TEL/Janus kinase 2 (JAK2), and
TEL/neurotrophin-3 receptor (TRKC). Plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were elevated by TEL/PDGFR and TEL/JAK2. However, all of the fusions tested efficiently induced MPD in mice genetically deficient for both GM-CSF and IL-3,
demonstrating that these cytokines are not necessary for the
development of disease in this model system. Furthermore, in
experiments using normal marrow transduced with TEL/PDGFR retrovirus
mixed with marrow transduced with an enhanced green fluorescent protein
(EGFP) retrovirus, the MPD induced in these mice demonstrated
minimal stimulation of normal myelopoiesis by the
TEL/PDGFR-expressing cells. In contrast, recipients of mixed
GM-CSF-transduced and EGFP-transduced marrow exhibited significant
paracrine expansion of EGFP-expressing cells. Collectively, these data
demonstrate that, although cytokine levels are elevated in murine bone
marrow transplant models of leukemia using tyrosine kinase fusion
oncogenes, GM-CSF and IL-3 are not required for myeloproliferation by
any of the oncogenes tested.
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