SOCS1 Cooperates with FLT3-ITD In the Development of Myeloproliferative Disease by Promoting the Escape From External Cytokine Control.

Abstract 1054

Activating mutations of FLT3 such as FLT3-ITD are frequently found in AML patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control, which regulates normal hematopoiesis. We have recently demonstrated that FLT3-ITD, when localized to the endoplasmic reticulum, aberrantly activates STAT5. Here we show that one of the target genes induced by STAT5 is SOCS1, a potent negative regulator of cytokine signaling and known tumor suppressor gene. Importantly, a significantly increased SOCS1 expression was found in FLT3-ITD+ AML. While SOCS1 expression in murine bone marrow severely impaired cytokineinduced colony growth, it failed to inhibit FLT3-ITD supported colony growth, indicating resistance of FLT3-ITD to SOCS1. Furthermore, SOCS1 co-expression inhibited interferon-γ signaling and protected FLT3-ITD hematopoietic cells from interferon-γ mediated growth inhibitory effects. In a murine bone marrow transplantation model, the co-expression of SOCS1 and FLT3-ITD significantly shortened the latency of a myeloproliferative disease compared to FLT3-ITD alone (p<0.01). Mechanistically, SOCS proteins shield FLT3-ITD from external cytokine control, thereby promoting malignant transformation. The data demonstrate that SOCS1 acts as a conditional oncogene, providing novel molecular insights into cytokine resistance in oncogenic transformation. Restoring cytokine control may provide a new way of therapeutic intervention.