The Inflammatory Cytokines In AML BM Microenvironment

PART 1Leukemic progenitors-derived Il-36γ induces an immunosuppressive microenvironment favoring leukemic progression and relapseA minority of leukemic progenitors(LPs)remodel hematopoietic microenvironment to facilitate leukemic progression or relapse,yet the underlying mechanisms remain poorly defined.Here,we show that a paracrine action of PML/RARα+LPs-derived Il-36y supports the leukemic progression at the critical phase through activating inflammatory monocytes(IMs)in bone marrow.Mechanistically,Il-36y stimulates Ccl3 synthesis,which in turn elaborates with Il-36y to activate IMs that support LPs’ proliferation and suppress a CD8+T cells-dependent immunorejection.Likewise,a strong Il-36γ/Ccl3 induction occurs to MLL/AF9+LPs post-chemotherapy,which promotes leukemic relapse by sustaining IMsCD8+T cells repressive axis.Collectively,we characterize a proinflamamtory feature of LPs in creating an immunopermissive microenvironment,implicating Il-36γ/Ccl3-IMs axis as a druggable target for restoring immunosurveillance against leukemia.PART 2Leukemic IL-17RB signaling regulates leukemic survival and chemo-resistanceSecreted proteins provide crucial signals that have been implicated in the development of leukemias bearing translocations of the mixed lineage leukemia(MLL)gene in the bone marrow microenvironment.Here we identify aberrant expressions of inflammatory interleukin-17B(IL-17B)and its receptor IL-17RB in human and mouse AML cells,which were further increased after exposure to chemotherapy.Interestingly,silencing of the IL17B or IL-17RB led to significant suppression of leukemic cell survival and disease progression in vivo.Moreover,IL-17B-IL-17RB axis protected leukemic cells from chemotherapeutic agent-induced apoptotic effects.Mechanistic studies revealed that IL-17B promoted AML cell survival by enhancing ERK,NF-κB phosphorylation and the expression of anti-apoptotic protein Bcl-2,which were reversed by small-molecule inhibitors.Thus,the inhibition of IL-17B/IL-17RB may be a valid strategy to enhance sensitivity and therapeutic benefit of AML chemotherapy.