NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia (CLL). ... more 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 signa...
Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current... more Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced a...
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of m... more Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of malignant B lymphocytes in the blood, bone marrow, spleen, and lymph nodes. This process is associated with constitutively activated B cell receptor (BCR) signaling, and interference with BCR signaling provides therapeutic benefit. Specifically, the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib prevents BTK tyrosine phosphorylation and thereby interferes with pathways downstream of BCR. It has shown high clinical response rates in patients with relapsed and refractory CLL, including patients with adverse cytogenetic profiles. Despite the high response rates achieved by ibrutinib, the drug has important limitations. Ibrutinib treatment induces a redistribution of CLL cells from protected niches to the peripheral blood, and the cellular response to ibrutinib is slow and often incomplete. Further, there is no evidence that a cure can be achieved, and drug discontinuation (e.g., due ...
NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia (CLL). ... more 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 signa...
Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current... more Deregulation of NOTCH2 signaling is implicated in a wide variety of human neoplasias. The current concept of targeting NOTCH is based on using gamma secretase inhibitors (GSI) to regulate the release of the active NOTCH intracellular domain. However, the clinical outcome of GSI remains unsatisfactory. Therefore we analyzed human solid tumor derived cell lines for their nuclear NOTCH activity and evaluated the therapeutic potential of the NOTCH2 transactivation inhibitor gliotoxin in comparison to the representative GSI DAPT. Electrophoretic mobility shift assays (EMSA) were used as a surrogate method for the detection of NOTCH/CSL transcription factor complexes. The effect of gliotoxin on cell viability and its clinical relevance was evaluated in vitro and in a melanoma xenograft mouse model. Cell lines derived from melanoma (518A2), hepatocellular carcinoma (SNU398, HCC-3, Hep3B), and pancreas carcinoma (PANC1) express high amounts of nuclear NOTCH2. Gliotoxin efficiently induced a...
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of m... more Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of malignant B lymphocytes in the blood, bone marrow, spleen, and lymph nodes. This process is associated with constitutively activated B cell receptor (BCR) signaling, and interference with BCR signaling provides therapeutic benefit. Specifically, the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib prevents BTK tyrosine phosphorylation and thereby interferes with pathways downstream of BCR. It has shown high clinical response rates in patients with relapsed and refractory CLL, including patients with adverse cytogenetic profiles. Despite the high response rates achieved by ibrutinib, the drug has important limitations. Ibrutinib treatment induces a redistribution of CLL cells from protected niches to the peripheral blood, and the cellular response to ibrutinib is slow and often incomplete. Further, there is no evidence that a cure can be achieved, and drug discontinuation (e.g., due ...
Uploads
Papers by Mohammad Araghi