The highly conserved Hedgehog/GLI signaling pathway regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis and the hematopoietic system by controlling cell fate decisions, stem cell self-renewal, and activation. Loss of negative control of Hedgehog signaling contributes to tumor pathogenesis and progression. In the classical view of canonical Hedgehog signaling, Hedgehog ligand binding to its receptor Patched culminates in the activation of the key pathway activator Smoothened, followed by activation of the GLI transcription factors. Its essential function and druggability render Smoothened well suited to therapeutic intervention. However, recent evidence suggests a critical role of Smoothened-independent regulation of GLI activity by several other signaling pathways including the PI3K/AKT and RAS/RAF/MEK/ERK axes. In addition, the contribution of canonical Hedgehog signaling via Patched and Smoothened to normal and malignant hematopoiesis has been the subject of recent controversies. In this review, we discuss the current understanding and controversial findings of canonical and noncanonical GLI activation in hematological malignancies in light of the current therapeutic strategies targeting the Hedgehog pathway.
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