Small Molecule Inhibitors of Wnt/β-Catenin/Lef-1 Signaling Induces Apoptosis in Chronic Lymphocytic Leukemia Cells In Vitro and In Vivo

Gandhirajan, Rajesh Kumar; Staib, Peter; Minke, Katharina; Gehrke, Iris; Plickert, Günther; Schlösser, Axel; Schmitt, E.; Hallek, Michael; Kreuzer, Karl‐Anton

doi:10.1593/neo.91972

Cited by 112 publications

(115 citation statements)

References 31 publications

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“…We examined the expression of an expanded set of Wnt pathway members and well-studied targets (supplemental Tables 4 and 5 for the gene list). [20][21][22] Consistent with previous reports, 6,8,9 we found LEF1, a canonical target of the Wnt pathway, to be the most significantly differentially overexpressed messenger RNA in CLL compared with normal B cells (ranked first of 20 765 features, BH-FDR #0.05; supplemental Table 4). We confirmed LEF1 overexpression in CLL cells at the protein level (supplemental Figure 3).…”

Section: The Wnt Pathway Is Transcriptionally and Functionally Hyperasupporting

confidence: 90%

“…[6][7][8][9] We confirmed this finding through the comparison of a large gene For personal use only. on May 11, 2018.…”

Section: The Wnt Pathway Is Transcriptionally and Functionally Hyperasupporting

confidence: 76%

“…2 These findings complement the previous observations of highly dysregulated gene expression and hypermethylation of Wnt pathway genes, as well as of the key pathway member LEF1 as a CLL risk loci identified by genome-wide association. 1,[6][7][8][9][10][11][12][13] The Wnt pathway is critical for the proliferation and cell fate determination of many cell types, including B cells. 14 The discovery of multiple mutated Wnt pathway members motivated us to query the role of pathway member mutations in altering signaling and cell survival.…”

Section: Introductionmentioning

confidence: 99%

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Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

Wang

Shalek

Lawrence

et al. 2014

Blood

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Section: The Wnt Pathway Is Transcriptionally and Functionally Hyperasupporting

confidence: 90%

“…[6][7][8][9] We confirmed this finding through the comparison of a large gene For personal use only. on May 11, 2018.…”

Section: The Wnt Pathway Is Transcriptionally and Functionally Hyperasupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

Wang

Shalek

Lawrence

et al. 2014

Blood

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“…This is of profound importance given the fact that the Wnt/ b-catenin pathway is aberrantly activated in CLL and contributes to the antiapoptotic and mitogenic nature of B-CLL cells. [70][71][72] In our study, we showed that AEB071 treatment at lower doses mediated GSK3-b dephosphorylation, which correlated with reduced expression of b-catenin as well as its downstream transcriptional targets c-Myc, Cyclin D1, and CD44 at both protein and transcript levels. Given this novel finding, pursuing AEB071 as a therapeutic agent that can target Wnt/b-catenin pathway in CLL is worthwhile and may prove to have significant therapeutic benefit in CLL patients.…”

Section: Org Frommentioning

confidence: 54%

PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

El‐Gamal¹,

Williams²,

LaFollette³

et al. 2014

Blood

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Key Points• AEB071 demonstrates preclinical in vitro and in vivo activity against CLL independent of survival signaling and stromal cell protection.• AEB071 can either inhibit or activate the WNT pathway emphasizing the importance of pharmacodynamic monitoring in its development.Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-b (PKC-b) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters b-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-b has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted. (Blood. 2014;124(9):1481-1491) IntroductionChronic lymphocytic leukemia (CLL) is one of the most common types of adult leukemia and is currently incurable. Decades of research into the biology of CLL and other B-cell malignancies has brought forth B-cell receptor (BCR) signaling as a common required driving force in the survival and proliferation of these tumor cells. Several survival pathways involved in BCR signaling, including the phosphatidylinositol 3-kinase (PI3K), nuclear factor-kB (NF-kB), and mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinase (ERK), are constitutively active in the lymph node and bone marrow compartment of CLL where disease expansion occurs. [1][2][3] Efforts to target BCR signaling with therapeutic agents which reversibly inhibit PI3K-d 4,5 or irreversibly inhibit Bruton tyrosine kinase (BTK) 6-8 have shown significant clinical activity in CLL, including those with high-risk genomic disease, and are currently in phase 3 studies. Protein kinase C-b (PKC-b) is an immediate downstream target of BTK that has recently been shown to be overexpressed in CLL 9 and is essential to the in vivo development of CLL in Em-TCL1 mice. 10 In B cells, PKC-b is thought to be the predominant PKC isoform mediating BCRdependent NF-kB activation.11-13 Downstream of PKC-b, IkB kinase and caspase recruitment domain-containing protein 11 (CARD11 [also known as CARMA1]) are phosphorylated, le...

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“…Recently, several pharmacological inhibitors or small molecules have been shown to efficiently induce apoptosis of chronic lymphocytic leukemia cells in vitro through their interaction with LEF1. 32,33 These findings implicate that LEF1 may be a potential therapeutic target in the future for patients with chronic lymphocytic leukemia.…”

Section: Discussionmentioning

confidence: 85%

Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

et al. 2011

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Lymphoid-enhancer-binding factor 1 (LEF1), coupling with b-catenin, functions as a key nuclear mediator of WNT/b-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5À cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5 þ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of b-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear b-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic lymphoma suggest that the pro-survival function of LEF1 in this disease may be independent of WNT/b-catenin signaling.

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Small Molecule Inhibitors of Wnt/β-Catenin/Lef-1 Signaling Induces Apoptosis in Chronic Lymphocytic Leukemia Cells In Vitro and In Vivo

Abstract: We have demonstrated that targeting lef-1 is a new and selective therapeutic approach in CLL. CGP049090 or PKF115-584 may be attractive compounds for CLL and other malignancies that deserve further (pre)clinical evaluation.

Cited by 112 publications

References 31 publications

Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

Somatic mutation as a mechanism of Wnt/β-catenin pathway activation in CLL

PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

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