The Functional And Mechanistic Study Of RIG-â…  In Restricting The Proliferation Of Myeloid Leukemia Cells

RIG-Ⅰ（Retinoid acid inducible gene I）, cloned and named by Shanghai Institute ofHematology, is up-regulated in the progression of ATRA induced differentiation of acutemyeloied leukaemia（APL）cell line NB4. In2004, investigators from Japan found thatRIG-Ⅰ acts as a pattern recognition receptor by detecting viral RNA and inducing innateimmunity. Based on this study, more and more works have been focused on elucidatingthe innate immunity function of RIG-Ⅰ and the related mechanisms. Our lab has focusedthe role of RIG-Ⅰ as a possible regulater of proliferation and differentiation of normal andleukemic myeloid cells. RIG-Ⅰ was found as an essential regulator of normal myeloid celldifferentiation in our previous study. Moreover, we have also shown that RIG-Ⅰ canaugment STAT1activation to restrict leukemic cell proliferation. This study continues ourinvestigation of the RIG-Ⅰ-related mechanism in restraining myeloid leukemic cellproliferation and of the function of RIG-Ⅰ during ATRA induced differentiation of APLcells, considering the possibility of finding new molecular target for the treatment ofmultiple types of actue myeloid leukemia. This study has generated the findings asfollows:1) RIG-Ⅰ inactivates mTOR via AKT, but not IPS-1, pathway in normal and leukemicmyeloid cells.2) RIG-Ⅰ targets Src to inactivate AKT-mTOR pathway.3) RIG-Ⅰ reduction contributes to AKT hyperactivation in primary AML blasts.4) RIG-Ⅰ CARDs and PxxP motif cooperate to modulate Src and AKT interaction.5) Rig-I inhibits Gm-csf-stimulated Src-Akt activation and proliferation of myeloidprogenitors.6) Rig-I depends on PxxP motif to inhibit Akt-mTor and leukemic propagation in vivo.In general, our study revealed that RIG-Ⅰ inhibit AKT-mTOR signaling pathway through Src to restrain leukemic propagation in a PxxP motif dependent manner.