File:Cancers-13-05722-g002-550.webp

English: Figure 2. Current immunotherapeutic approaches targeting leukemic stem cells in AML patients. TIM-3 is a membrane bound glycoprotein and immunoreceptor expressed on both LSCs and cytotoxic CD4+ and CD8+ T-cells. It can be addressed by monoclonal antibodies (MB453 or PDR001) and bispecific directed CAR-T cells against CD13 and TIM-3. GPR56, a G-protein coupled transmembrane receptor, can be overexpressed in LSCs causing upregulation of leukemia driving transcription factor HOXA1. CD44 is an adhesion molecule, which physically interacts with the transmembrane protein CXCR4 and activated by CXCL12, which is crucial for anchorage of LSCs in the bone marrow niche. Inhibition of CD44 overcomes resistance to BCL-2 inhibitor venetoclax whereas CXCR4 can directly be inhibited by plerixafor, leading to mobilization of LSCs from the bone marrow niche [197]. CD47 is an integrin associated membrane protein and able to suppress macrophages and thus preventing eliminating of LSCs. The CD47 directed monoclonal antibody magrolimab could disrupt the connection between CD47 on LSC and SIRPalpha on macrophages. CD123 as interleukin 3 receptor can be targeted by bispecific CD3/CD123 antibodies to redirect T-cell to LSCs. CD70 as a ligand of the TNF superfamily receptor CD27 can be hindered from binding by monoclonal antibody cusatuzumab or CD70 directed CAR-T cells. Same approaches are illustrated for CLL-1 receptor. SHH and MAPK signaling is illustrated since they represent highly conserved pathways in LSCs which mainly contribute to maintenance and cell proliferation. MAPK is known to activate integrated stress response signaling which promotes cellular recovery and restore homeostasis. The transcription factor FOXM1 is crucial for maintaining, survival, and renewing of LSCs, which is activated by b-catenin/WNT signaling. Created with BioRender.com. Abbreviations: TIM-3 T cell immunoglobulin and mucin-domain containing-3; AML acute myeloid leukemia; LSC leukemic stem cell; CAR-T chimeric antigen receptor t cell; GPR56 adhesion G protein–coupled receptor 56; HOXA1 Homeobox A1; CXCR4 C-X-C chemokine receptor type 4; CXCL12 C-X-C chemokine ligand type 12; BCL-2 b-cell lymphoma-2; TNF tumor necrosis factor; CLL-1 C-type lectin domain family 12 member A; SHH sonic hedgehog; MAPK Mitogen-activated protein; FOXM1 Forkhead Box Protein M1; VEN Venetoclax.