Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

López‐Guerra, Mònica; Xargay-Torrent, Sílvia; Fuentes, Patricia; Roldán, Jocabed; González-Farré, Blanca; Rosich, Laia; Silkenstedt, Elisabeth; García-León, María J.; Lee-Vergés, Eriong; Giménez, Neus; Giró, Ariadna; Aymerich, Marta; Villamor, Neus; Delgado, Julio; López‐Guillermo, Armando; Puente, Xosé S.; Campo, Elı́as; Toribio, Marı́a L.; Colomer, Dolors

doi:10.1038/s41388-019-1053-6

Cited by 25 publications

(27 citation statements)

References 46 publications

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“…Thus, NOTCH1 mutations are dependent on the presence of Notch ligands in the microenvironment and activate processes such as cell migration, invasion and angiogenesis. 33,34 BCR and NOTCH1 pathways are functionally linked, mutually enhancing their activation. 35 MYD88 mutations activate the NF-κB pathway in response to TLR ligands, increasing the cytokine release involved in recruiting stromal and T cells.…”

Section: The Microenvironment In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

et al. 2020

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Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies. In this review we provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients.

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Section: The Microenvironment In Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

et al. 2020

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“…RO4929097 inhibited the NOTCH3/NR4A1 axis, upregulated the NOTCH2/FCER2 (CD23) axis, and enhanced the NOTCH2/CSL transcription factor complex ( Figure 5 B, right panel), which stands in sharp contrast to the effect of gliotoxin. The NOTCH1 target gene MYC was downregulated by RO4929097 ( Figure 5 B, right panel) [ 9 , 43 , 44 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…NOTCH1 is not detectable in nuclear NOTCH/CSL transcription factor complexes in CLL cells [ 7 , 8 , 18 , 32 ]. However, NOTCH1 is frequently mutated and/or overexpressed in advanced stage CLL cells, where it has a CLL-driving role by regulating MYC expression [ 8 , 9 , 16 , 17 , 43 , 44 , 45 ]. In this context, NOTCH1 may indirectly account for the relative GSI sensitivity of NOTCH2, keeping in mind that active NOTCH1 is a positive regulator of the NOTCH2 gene in CLL cells ( Figure 5 G) [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL

Hubmann

Schnabl

Araghi

et al. 2020

Cells

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NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia (CLL). We compared the anti-neoplastic effects of the nuclear NOTCH2 inhibitor gliotoxin and the pan-NOTCH γ-secretase inhibitor RO4929097 in primary CLL cells with special emphasis on the individual roles of the different NOTCH receptors. Gliotoxin rapidly induced apoptosis in all CLL cases tested, whereas RO4929097 exerted a variable and delayed effect on CLL cell viability. Gliotoxin-induced apoptosis was associated with inhibition of the NOTCH2/FCER2 (CD23) axis together with concomitant upregulation of the NOTCH3/NR4A1 axis. In contrast, RO4929097 downregulated the NOTCH3/NR4A1 axis and counteracted the spontaneous and gliotoxin-induced apoptosis. On the cell surface, NOTCH3 and CD23 expression were mutually exclusive, suggesting that downregulation of NOTCH2 signaling is a prerequisite for NOTCH3 expression in CLL cells. ATAC-seq confirmed that gliotoxin targeted the canonical NOTCH signaling, as indicated by the loss of chromatin accessibility at the potential NOTCH/CSL site containing the gene regulatory elements. This was accompanied by a gain in accessibility at the NR4A1, NFκB, and ATF3 motifs close to the genes involved in B-cell activation, differentiation, and apoptosis. In summary, these data show that gliotoxin recovers a non-canonical tumor-suppressing NOTCH3 activity, indicating that nuclear NOTCH2 inhibitors might be beneficial compared to pan-NOTCH inhibitors in the treatment of CLL.

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“…Recent advances regarding DLL4-Notch 1 signaling in CLL revealed its importance as a promising therapeutic target [ 83 ]. In fact, DLL4 is widely expressed in lymph-node histiocytes and its interaction with Notch 1 increases cell proliferation, migration and neo-angiogenesis, in particular in CLL cases carrying Notch 1 mutations.…”

Section: Notchmentioning

confidence: 99%

“…In fact, DLL4 is widely expressed in lymph-node histiocytes and its interaction with Notch 1 increases cell proliferation, migration and neo-angiogenesis, in particular in CLL cases carrying Notch 1 mutations. This binding could be antagonized using specific anti-Notch 1 monoclonal antibodies [ 83 ]. These data also require further investigation, but it seems conceivable that the use of monoclonal antibodies appears to be a possible therapeutic strategy in CLL patients with mutated Notch 1 and aggressive disease [ 84 ] ( Figure 1 ).…”

Section: Notchmentioning

confidence: 99%

Role of Notch Receptors in Hematologic Malignancies

Gragnani

Lorini

Marri

et al. 2020

Cells

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Notch receptors are single-pass transmembrane proteins that play a critical role in cell fate decisions and have been implicated in the regulation of many developmental processes. The human Notch family comprises of four receptors (Notch 1 to 4) and five ligands. Their signaling can regulate extremely basic cellular processes such as differentiation, proliferation and death. Notch is also involved in hematopoiesis and angiogenesis, and increasing evidence suggests that these genes are involved and frequently deregulated in several human malignancies, contributing to cell autonomous activities that may be either oncogenic or tumor suppressive. It was recently proposed that Notch signaling could play an active role in promoting and sustaining a broad spectrum of lymphoid malignancies as well as mutations in Notch family members that are present in several disorders of T- and B-cells, which could be responsible for altering the related signaling. Therefore, different Notch pathway molecules could be considered as potential therapeutic targets for hematological cancers. In this review, we will summarize and discuss compelling evidence pointing to Notch receptors as pleiotropic regulators of hematologic malignancies biology, first describing the physiological role of their signaling in T- and B-cell development and homeostasis, in order to fully understand the pathological alterations reported.

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Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

Cited by 25 publications

References 46 publications

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL

Role of Notch Receptors in Hematologic Malignancies

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