Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma

Hegde, Ganapati V.; Munger, Corey M.; Emanuel, Katy; Joshi, Avadhut D.; Greiner, Timothy C.; Weisenburger, Dennis D.; Vose, Julie M.; Joshi, Shantaram S.

doi:10.1158/1535-7163.mct-07-2118

Cited by 77 publications

(65 citation statements)

References 39 publications

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“…Furthermore, downregulation of GLI transcription factors with the use of antisense oligonucleotides significantly reduced cyclin D1 and BCL-2 transcript levels, decreased proliferation of MCL cells, and increased their susceptibility to chemotherapy. 96 These results indicate a role for SHH-GLI signaling in MCL proliferation and identify the hedgehog pathway as a potential therapeutic target in MCL Antiapoptotic BCL-2 family proteins BCL-2 family proteins are key regulators of apoptosis, determining cellular fate in response to numerous insults ( Figure 6). 97 The BCL-2 pathway is deregulated in MCL; high-level copy number gains of the BCL2 locus at 18q21.3 are frequent, 31 high MCL1 expression is common in more aggressive tumors 98 and can be increased by AKT/mTOR signaling, and BCL-X L overexpression has been linked to constitutive activation of the NF-B pathway.…”

Section: Hedgehog Pathwaymentioning

confidence: 85%

Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

Pérez-Galán

Dreyling

Wiestner

2011

Blood

358

310

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Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma of which at least a subset arises from antigen-experienced B cells. However, what role antigen stimulation plays in its pathogenesis remains ill defined. The genetic hallmark is the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. Secondary genetic events increase the oncogenic potential of cyclin D1 and frequently inactivate DNA damage response pathways. In combination these changes drive cell-cycle progression and give rise to pronounced genetic instability. Several signaling pathways contribute to MCL pathogenesis, including the often constitutively activated PI3K/AKT/ mTOR pathway, which promotes tumor proliferation and survival. WNT, Hedgehog, and NF-B pathways also appear to be important. Although MCL typically responds to frontline chemotherapy, it remains incurable with standard approaches. Proteasome inhibitors (bortezomib), mTOR inhibitors (temsirolimus), and immunomodulatory drugs (lenalidomide) have recently been added to the treatment options in MCL. The molecular basis for the antitumor activity of these agents is an area of intense study that hopefully will lead to further improvements in the near future. Given its unique biology, relative rarity, and the difficulty in achieving long-lasting remissions with conventional approaches, patients with MCL should be encouraged to participate in clinical trials. (Blood. 2011; 117(1):26-38) Diagnosis, clinical course, and the origin of MCLMantle cell lymphoma (MCL), a mature B-cell neoplasm defined as a distinct entity in the early 1990s constitutes ϳ 6% of all non-Hodgkin lymphomas (NHLs). 1-4 MCL is typically disseminated at presentation, with a leukemic component in 20%-30% of patients. Classic and blastoid variants are recognized, the latter associated with inferior clinical outcome ( Figure 1A). The genetic hallmark of MCL is the translocation t(11;14)(q13;q32) leading to aberrant expression of cyclin D1, which is not typically expressed in normal lymphocytes ( Figure 1B). However, cyclin D1-negative cases having typical morphology and gene expression profile have been described and often show overexpression of cyclin D2 or D3. 5 Recently, SOX11 has been described as a diagnostic maker that is equally expressed in D1-positive and D1-negative MCL. 6,7 MCL is one of the most difficult to treat B-cell lymphomas. Although conventional chemotherapy induces high-remission rates in previously untreated patients, relapse within a few years is common, contributing to a rather short median survival of 5-7 years. 8,9 The best predictor of survival is tumor proliferation ( Figure 1C). 5 Intensification of first-line treatment has improved progression-free survival, but no curative regimen has been defined so far. 2,3 In MCL, as in chronic lymphocytic leukemia (CLL), the variable region of the expressed immunoglobulin heavy chain gene (IGHV) displays either germline configuration (Ig-unmutated), as found in naive B cells, or contains somatic mutations (Ig-mutated), indicat...

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Section: Hedgehog Pathwaymentioning

confidence: 85%

Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

Pérez-Galán

Dreyling

Wiestner

2011

Blood

358

310

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“…Active paracrine Hedgehog signaling has been shown in other B-cell malignancies (30,31). Hedgehog pathway components are present in Burkitt lymphoma cells.…”

Section: Discussionmentioning

confidence: 99%

Noncanonical Regulation of the Hedgehog Mediator GLI1 by c-MYC in Burkitt Lymphoma

Yoon

Gallant

Lamm

et al. 2013

Molecular Cancer Research

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Although Hedgehog signaling plays a major role in GLI1 transcription, there is now evidence suggesting that other pathways/genes, such as c-MYC, may also regulate GLI1 expression. We initiated studies in Burkitt lymphoma cells, which constitutively express c-MYC due to a chromosomal translocation, to determine whether Hedgehog or c-MYC regulates GLI1 expression. We show that all Burkitt lymphoma cell lines tested express GLI1, PTCH1, and SMO and that five of six Burkitt lymphomas express GLI1. Exposure to Sonic or Indian Hedgehog or cyclopamine (SMO inhibitor) does not modulate GLI1 expression, cell proliferation, or apoptosis in most Burkitt lymphoma cell lines. Sequence analysis of PTCH1, SMO, and SuFu failed to show mutations that might explain the lack of Hedgehog responsiveness, and we did not detect primary cilia, which may contribute to it. We show that c-MYC interacts with the 5 0 -regulatory region of GLI1, using chromatin immunoprecipitation (ChIP) assay, and E-box-dependent transcriptional activation of GLI1 by c-MYC in NIH3T3 and HeLa cells. The c-MYC small-molecule inhibitor 10058-F4 downregulates GLI1 mRNA and protein and reduces the viability of Burkitt lymphoma cells.

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“…12,94 In mantle cell lymphoma, preliminary work has shown that mantle cell lymphoma cell lines and primary human samples had increased expression of Hh pathway components compared with normal B cells and were partially responsive to HH ligand or its pharmacologic inhibition. 95 Direct inhibition of the downstream effectors GLI1 and GLI2 had the most profound effect on mantle cell lymphoma cells, indicating that, although canonical Hh signaling may be involved in mantle cell lymphoma, there are probably other factors driving GLI1 and GLI2 expression.…”

Section: Lymphoma and Cllmentioning

confidence: 97%

Targeting hedgehog in hematologic malignancy

Irvine

Copland

2012

Blood

127

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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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Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma

Cited by 77 publications

References 39 publications

Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era

Noncanonical Regulation of the Hedgehog Mediator GLI1 by c-MYC in Burkitt Lymphoma

Targeting hedgehog in hematologic malignancy

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