Induction of myeloproliferative disease in mice by tyrosine kinase fusion oncogenes does not require granulocyte-macrophage colony-stimulating factoror interleukin-3

Tyrosine kinase fusion oncogenes that occur as a result of chromosomal tran slocations have been shown to activate proliferative and antiapoptotic path ways in leukemic cells, but the importance of autocrine and paracrine expre ssion 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 exp eriments, and murine models of leukemia. This report demonstrates that inte rleukin (IL)-3 plasma levels are elevated in myeloproliferative disease (MP D) caused by the TEL/ tyrosine kinase fusions TEL/platelet-derived growth f actor beta receptor (PDGF betaR), TEL/Janus kinase 2 (JAK2), and TEL/neurot rophin-3 receptor (TRKC). Plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were elevated by TEL/PDGF betaR and TEL/JAK2. Howeve r, all of the fusions tested efficiently induced MPD in mice genetically de ficient for both GM-CSF and IL-3, demonstrating that these cytokines are no t necessary for the development of disease in this model system. Furthermor e, in experiments using normal marrow transduced with TEL/PDGF betaR retrov irus mixed with marrow transduced with an enhanced green fluorescent protei n (EGFP) retrovirus, the MPD induced in these mice demonstrated minimal sti mulation of normal myelopoiesis by the TEL/PDGF betaR-expressing cells. In contrast, recipients of mixed GM-CSF-transduced and EGFP-transduced marrow exhibited significant paracrine expansion of EGFP-expressing cells. Collect ively, these data demonstrate that, although cytokine levels are elevated i n murine bone marrow transplant models of leukemia using tyrosine kinase fu sion oncogenes, GM-CSF and IL-3 are not required for myeloproliferation by any of the oncogenes tested. (Blood, 2001;97:1435-1441) (C) 2001 by The Ame rican Society of Hematology.