Expansion of Bcr-Abl-Positive Leukemic Stem Cells Is Dependent on Hedgehog Pathway Activation

Abstract

Resistance of Bcr-Abl-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CML) can cause relapse of disease and might be the origin for emerging drug-resistant clones. In this study, we identified Smo as a drug target in Bcr-Abl-positive LSCs. We show that Hedgehog signaling is activated in LSCs through upregulation of Smo. While Smo(-/-) does not impact long-term reconstitution of regular hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias was abolished in the absence of Smo expression. Pharmacological Smo inhibition reduced LSCs in vivo and enhanced time to relapse after end of treatment. Our results indicate that Smo inhibition might be an effective treatment strategy to reduce the LSC pool in CML.

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.…”

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

“…Combined therapy with TKIs plus agents that target other aspects of LSCs, such as hedgehog pathway inhibitors, is one strategy to control LSC proliferation and potentially provide deeper molecular responses and prevent relapse after TKI cessation. The hedgehog signaling pathway is activated in LSCs derived from patients with CML and is required for LSC maintenance [63,64]; combined treatment with nilotinib and the smoothened inhibitor LDE225 depleted LSCs and reduced LSC bone marrow engraftment in a mouse model of CML-CP [65]. A phase 1 trial of nilotinib and LDE225 in patients with CML-CP or CML-AP who have resistance to prior TKIs is ongoing.…”

Cancer Stem Cells: Formidable Allies of Cancer

“…Various studies have shown that PTEN/PI3K/Akt/Wnt signalling axis plays a vital role in maintenance of normal as well as malignant stem cell homeostasis [98][99][100], [88], [101][102][103][104]. Similarly, hedgehog signalling has been shown to play a role in regulating normal and malignant stem cells [105][106][107]. Notch signalling is known to regulate CSC maintenance [108,109].…”