Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells

Desch, Petra; Asslaber, Daniela; Kern, Daniela; Schnidar, Harald; Mangelberger, Doris; Alinger, Beate; Stoecher, Markus; Hofbauer, Sebastian W.; Neureiter, Daniel; Tinhofer, Ingeborg; Aberger, Fritz; Hartmann, Tanja N.; Greil, Richard

doi:10.1038/onc.2010.243

Cited by 71 publications

(74 citation statements)

References 63 publications

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“…96 In contrast, Desch et al found that key participants of the Hh signaling cascade (including SMO and GLI1) were not differentially expressed in B-CLL cells over normal B cells. 97 In addition, in their studies, SMO inhibition alone did not influence B-CLL cell survival in vitro. However, GANT61 (a direct Gli1 inhibitor) caused significant apoptosis in B-CLL cells but not normal B cells in vitro, which could be rescued by stromal coculture but not recombinant SHH ligand alone.…”

Section: Lymphoma and Cllmentioning

confidence: 99%

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Targeting hedgehog in hematologic malignancy

Irvine

Copland

2012

Blood

126

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The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology.

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Section: Lymphoma and Cllmentioning

confidence: 99%

“…This suggests that other signaling pathways converging on GLI1 expression were responsible. 97 Decker et al recently demonstrated that both Hh mediator expression and SMO inhibitor responsiveness were variable in different patients. They found that 60% of their CLL cohort responded to SMO inhibition.…”

Section: Lymphoma and Cllmentioning

confidence: 99%

Targeting hedgehog in hematologic malignancy

Irvine

Copland

2012

Blood

126

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“…In addition to Smo antagonists, other inhibitors were used to block Hh signaling like the small molecule inhibitor of GLI1 and GLI2 transcription factors, GANT61, which induced colon carcinoma cell death in a higher extent respect to the conventional Smo inhibitor cyclopamin [74] . The treatment with GANT61 reduced also the expression of the target gene Patched and decreased the viability of chronic lymphocytic leukemia cells [75] . Recently, the systemic antifungal itraconazole which failed to bind to Smo at the same binding site of cyclopamine, showed a potent antagonism for the Hh signaling pathway associated with anti-tumor activity in a mouse medulloblastoma allograft model [76] .…”

Section: Gpcrs Activated By Peptidesmentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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“…37 In our previous work, we could show that HH pathway inhibition by SMO inhibitors could block the expansion of murine lymphomas in vitro and in vivo. 16 In addition, human lymphoid malignancies, such as diffuse large B-cell lymphoma, 38 NPM-ALK-driven anaplastic large cell lymphoma, 39 mantle cell lymphoma, 40 43 Therefore, the aim of the present study was to identify biomarkers and clinical parameters, which can discriminate in between SMO-inhibitor responsive and resistant CLLs and to identify mechanisms of HH pathway activation in CLL. …”

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confidence: 99%

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

Decker

Zirlik

Djebatchie

et al. 2012

Blood

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Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMOinhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HHsignaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high GLI1 and PTCH1 transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects. (Blood. 2012;119(4):997-1007) Introduction B-cell chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western countries and is characterized by a progressive accumulation of functionally incompetent Blymphocytes in the peripheral blood, BM, and lymphoid organs. 1,2 Several prognostic markers such as Rai and Binet staging systems, 3,4 immunoglobulin V H gene mutational status, 5 -associated protein 70 (ZAP70) expression 6,7 and cytogenetic abnormalities 8 such as trisomy 12 and del 13q14 can be used to predict the survival outcome and the need for treatment of patients with CLL. 9 Despite encouraging new therapeutic strategies 10 CLL cannot be cured by conventional therapy at present, and only hematopoietic stem cell transplantation has led to complete and ongoing remissions in some patients. 11 The exact pathogenesis of this clinically heterogenous leukemia is still unknown, 12 but it is well established that B-CLL cells are habitually interacting with stromal cells, indicating the importance of the microenvironment for survival of CLL cells. [13][14][15] In our previous work, we demonstrated that the hedgehog (HH) ligands sonic (Shh), indian (Ihh), and desert (Dhh) are produced by stromal cells in lymphoid organs and that the BM promote expansion of murine lymphomas in vitro and in vivo. 16 HH ligands activate the transmembrane receptor PATCHED (PTCH), which abrogates the suppression of the 7-transmembranehelix protein SMOOTHENED (SMO), the key player for signal transduction of the canonical HH pathway. 17 SMO activation leads to production of activating forms of the glioma-associated oncoproteins 1-3 (GLI1-3), the H...

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Inhibition of GLI, but not Smoothened, induces apoptosis in chronic lymphocytic leukemia cells

Cited by 71 publications

References 63 publications

Targeting hedgehog in hematologic malignancy

Targeting hedgehog in hematologic malignancy

GPCRs and cancer

Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

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