Therapeutic Targeting Of Gli1 In Acute Myeloid Leukemia

Hematopoietic stem and progenitor cell (HSPCs) proliferation are tightly regulated during normal homeostasis. Recent data suggests that aberrantly activated signaling pathways such as Hedgehog (Hh), Notch, and Wnt occur during early hematopoietic oncogenesis. Gli genes (Gli1-3), known as Gli-code, encode Cys2-His2 zinc finger transcription factors governing the expression of pro-survival genes at the distal end of the Hh pathway (Hh→ PTCH1→ SMO→ GLI). These genes are tightly regulated in embryonic development. They are a common node of dysregulated activation through which many oncogenic signals, such as Hh, FLT3, PI3K-AKT, TGFβ, and RAS, converge. Hh-signaling critical for embryogenesis is mostly inactive in adult tissues; however, aberrant activation of the Hh/Gli has been implicated in cancer progression and chemotherapy resistance in AML. Activation of SMO triggers an intracellular …