Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia

Abstract

Although the role of Hedgehog (Hh) signalling in embryonic pattern formation is well established 1 , its functions in adult tissue renewal and maintenance remain unclear, and the relationship of these functions to cancer development has not been determined. Here we show that the lossof Smoothened (Smo), an essential component of the Hh pathway 2 , impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukaemia (CML) by the BCR-ABL1 oncoprotein 3 . Loss of Smo causes depletion of CML stem cells-the cells that propagate the leukaemia-whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, we show that the cell fate determinant Numb, which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacological inhibition of Hh signalling impairs not only the propagation of CML driven by wildtype BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. These data indicate that Hh pathway activity is required for maintenance of normal and neoplastic stem cells of the haematopoietic system and raise the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML 4,5 might be avoided by targeting this essential stem cell maintenance pathway.

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…However, it does not affect upstream Shh ligand expression. The shortcomings of CPN are its short half-life and off-target effects at higher doses (Lipinski et al, 2008; Zhao et al, 2009). Therefore, a more soluble and potent CPN derivative, IPI-926 (Saridegib), has been explored in clinical trials for basal cell carcinoma (BCC) and metastatic pancreatic cancer.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Mounting evidence indicate that hedgehog signaling is required for maintenance of cancer stem cell population (Dierks et al, 2008;Read et al, 2009;Zhao et al, 2009). For example, recent studies indicate that leukemia stem cells maintenance and expansion is dependent on hedgehog signaling (Dierks et al, 2008;Zhao et al, 2009).…”

“…For example, recent studies indicate that leukemia stem cells maintenance and expansion is dependent on hedgehog signaling (Dierks et al, 2008;Zhao et al, 2009). In the absence of Smo or treatment of cyclopamine, the hematopoietic stem cell population is dramatically reduced.…”

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“…It has been shown that multiple pathways are involved in the self-renewal and tumor progression of CSCs, including Notch, Wnt, Hedgehog and phosphatidyl-inositol-3 kinase (PI3K) etc (Taipale and Beachy, 2001;Reya and Clevers, 2005;Farnie and Clarke, 2007;Dubrovska et al, 2009;Zhao et al, 2009). The ERBB2 (HER2) gene is amplified in approximately 20-30% of human breast and gastric cancers, in which it is associated with aggressive disease and early development of metastasis (Slamon et al, 1989;Tanner et al, 2005;Yano et al, 2006).…”