(A) A very simplified scheme of the hedgehog signaling pathway. (Left) In the absence of ligand the Patched (PTCH1) receptor inhibits the activity of the smoothened (SMO) transmembrane protein. The GLI-1 (and GLI-2) transcription factor is kept in the cytosol by Suppressor of Fused (SUFU) and other proteins. (Right) Upon binding of hedgehog ligands, either SHH or IHH, to PTCH1, the inhibitory activity on SMO is relieved. Signaling downstream to SMO releases GLI-1 that translocases into the nucleus, binds to DNA, and regulates the expression of hedgehog target genes. (B) Proposed mechanisms of the positive effects of hedgehog ligands on T-ALL. Approximately 20% of T-ALLs secrete either SHH and IHH. These cytokines have both autocrine and paracrine effects. They bind to T-ALL cells and activate the hedgehog pathway, resulting in activation of GLI-1 and consequent upregulation of prosurvival and growth genes. In addition, SHH/IHH bind to thymic epithelium cells and induce the expression of T-ALL–promoting proteins such as the Notch ligand DLL4, interleukin 7 (IL-7), and vascular endothelial growth factor (VEGF).