Hence, we developed a novel strategy that combines both essential signals in 1 transgene by expressing the nonlymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T cells. c-MPL signaling activates pathways shared with conventional costimulatory and cytokine receptor signaling.
Our results indicated that (1) the expression of TEL-FGFR3 but not DeltaHLH-TEL-FGFR3 resulted in efficient focus formation in NIH/3T3 cells and conferred interleukin 3 independence to Ba/F3 cells by a constitutive tyrosine kinase activity probably through oligomerization by the HLH domain of TEL; (2) although effector proteins including classical mitogen-activated protein kinase (MAPK), p38 MAPK, phosphatidylinositol 3-kinase (PI3-K), mammalian target or rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT-3) and STAT-5 were activated in TEL-FGFR3 transformants, the growth of the transformants was inhibited by SU5402 (concentration that inhibits 50% [IC5)]=5 microM) and the PI3-K inhibitor, LY294002 (IC5)=10 microM) and wortmannin (IC50=5 microM), but not by U0126, SB203580, or rapamycin; and (3) injection of TEL-FGFR3 transformants induced lethal leukemia into syngeneic mice.
Deregulation of IL-3 receptor chain gene expression may provide a proliferative advantage to hematopoietic cells growing under conditions in which the cytokine is limiting and allow the development of a leukemia.
Bone marrow cells were studied prior to and after 3 days of IL-3 administration to assess changes in overall and leukemic progenitor cell [leukemia colony-forming unit (CFU-L)] proliferation, and progenitor cell sensitivity to 1-betad-arabinofuranosylcytosine.
Our data support the formulation that this subtype of leukemia may arise in part because of a chromosome translocation that activates the IL-3 gene, resulting in autocrine and paracrine growth effects.
The data suggest that activation of the IL-3 gene by the enhancer of the immunoglobulin heavy chain gene may play a central role in the pathogenesis of this leukemia and the associated eosinophilia.