Abstract
Objective. Fusion genes involving file platelet-derived growth factor receptor-beta (PDGFR beta) are found in a subgroup of myeloproliferative neoplasms, with one such fusion, Tel/PDGFR beta found in a subset or chronic myelomonocytic leukemia patients. Tel/PDGFR beta results in constitutive activation of several signaling pathways and induces a myeloproliferative disease in mice, with signals via tyrosines 579/581 identified as being important for this phenotype. In this study, we have used a tetracycline-regulated system to express wild-type and the mutated F2 Tel/PDGFR beta to identify the key signaling pathways, which drive Tel/PDGFR beta-induced differentiation of embryonic steal (ES) cells.
Materials and Methods. The leukemic oncogene Tel/PDGFR beta and Tel/PDGFR beta-F2 were inducibly expressed in ES cells and their effects on self-renewal, signal transduction, and gene expression patterns analyzed.
Results. Tel/PDGFR beta activated several major signal transduction pathways (signal transducers and activators of transcription [STAT] 3, STAT5 mitogen-activated protein kinases, phosphatidylinositol-3 kinase) in ES cells, but only specific inhibition of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) or STAT5 pathways was able to significantly prevent Tel/PDGFR beta-induced differentiation and restore ES-cell self-renewal. Inhibiting the tyrosine kinase activity of the oncogene using Gleevec or PDGFR beta inhibitor III also substantially prevented Tel/PDGFR beta-induced differentiation and its ability to upregulate key genes involved in myelopoiesis. Tyrosines 579/581 played a critical role in mediating signals via the Ras/ERK and STAT5 pathways, with dual targeting of the tyrosine kinase activity of Tel/PDGFR beta and the MEK/ERK pathway completely preventing Tel/PDGFR beta-induced differentiation.
Conclusion. These findings suggest that targeted disruption of key signaling pathways in combination with the tyrosine kinase activity of leukemic oncogenes, such as Tel/PDGFR beta, may result in more efficacious therapies for suppressing leukemic progression in the clinical setting.
Materials and Methods. The leukemic oncogene Tel/PDGFR beta and Tel/PDGFR beta-F2 were inducibly expressed in ES cells and their effects on self-renewal, signal transduction, and gene expression patterns analyzed.
Results. Tel/PDGFR beta activated several major signal transduction pathways (signal transducers and activators of transcription [STAT] 3, STAT5 mitogen-activated protein kinases, phosphatidylinositol-3 kinase) in ES cells, but only specific inhibition of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) or STAT5 pathways was able to significantly prevent Tel/PDGFR beta-induced differentiation and restore ES-cell self-renewal. Inhibiting the tyrosine kinase activity of the oncogene using Gleevec or PDGFR beta inhibitor III also substantially prevented Tel/PDGFR beta-induced differentiation and its ability to upregulate key genes involved in myelopoiesis. Tyrosines 579/581 played a critical role in mediating signals via the Ras/ERK and STAT5 pathways, with dual targeting of the tyrosine kinase activity of Tel/PDGFR beta and the MEK/ERK pathway completely preventing Tel/PDGFR beta-induced differentiation.
Conclusion. These findings suggest that targeted disruption of key signaling pathways in combination with the tyrosine kinase activity of leukemic oncogenes, such as Tel/PDGFR beta, may result in more efficacious therapies for suppressing leukemic progression in the clinical setting.
| Original language | English |
|---|---|
| Pages (from-to) | 111-121 |
| Number of pages | 11 |
| Journal | Experimental Hematology |
| Volume | 37 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2009 |
| Externally published | Yes |