Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia

Kamga, Paul Takam; Collo, Giada Dal; Midolo, Martina; Adamo, Annalisa; Delfino, Pietro; Mercuri, Angela; Cesaro, Simone; Mimiola, Elda; Bonifacio, Massimiliano; Andreini, Angelo; Chilosi, Marco; Krampera, Mauro

doi:10.1158/0008-5472.can-18-1617

Cited by 35 publications

(30 citation statements)

References 46 publications

(73 reference statements)

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“…We tested the hypothesis that inhibition of Notch signaling increases the sensitivity of FLT3/ITD + AML cells to TKIs, although the exact mechanisms that lead to the activation of Notch signaling upon TKI treatment require further investigation. Consistent with previous reports that combine Notch inhibition with anti-leukemic drugs in myeloma, 33 B-ALL 34,35 , and CLL, 36 our research supports the idea of dual inhibition of FLT3 and NOTCH signaling with small molecules as a potential strategy for FLT3/ITD + AML treatment.…”

Section: Discussionsupporting

confidence: 92%

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Li¹,

Li²,

Shang³

et al. 2020

Sig Transduct Target Ther

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Internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase-3 (FLT3) are the most frequent genetic alterations in acute myeloid leukemia (AML) and predict a poor prognosis. FLT3 tyrosine kinase inhibitors (TKIs) provide short-term clinical responses, but the long-term prognosis of FLT3/ITD + AML patients remains poor. Notch signaling is important in numerous types of tumors. However, the role of Notch signaling in FLT3/ITD + AML remains to be elucidated. In the current study, we found that Notch signaling was activated upon FLT3-TKI treatment in FLT3/ITD + cell lines and primary cells. As Notch signaling can be blocked by γ-secretase inhibitors (GSIs), we examined the combinatorial antitumor efficacy of FLT3-TKIs and GSIs against FLT3/ITD + AML and explored the underlying molecular mechanisms. As a result, we observed synergistic cytotoxic effects, and the treatment preferentially reduced cell proliferation and induced apoptosis in FLT3/ITD + AML cell lines and in primary AML cells. Furthermore, the combination of FLT3-TKI and GSI eradicated leukemic cells and prolonged survival in an FLT3/ITD + patient-derived xenograft AML model. Mechanistically, differential expression analysis suggested that CXCR3 may be partially responsible for the observed synergy, possibly through ERK signaling. Our findings suggest that combined therapies of FLT3-TKIs with GSI may be exploited as a potential therapeutic strategy to treat FLT3/ITD + AML.

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Section: Discussionsupporting

confidence: 92%

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Li¹,

Li²,

Shang³

et al. 2020

Sig Transduct Target Ther

View full text Add to dashboard Cite

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“…Thus, like many other signaling pathways in a biological system, the phenotypic outcome of Notch activity in regard to apoptosis is highly cell type and context dependent ( 17 ). Lymphocytes, including T and B cells, are known to express Notch ( 18 , 19 ), and Notch signaling plays critical roles in controlling lymphocyte function and cell fate in lymphocyte malignancies ( 20 , 21 ). Activating Notch mutations are found in about 60% of patients with T cell acute lymphoblastic leukemia (T-ALL) and across all T-ALL subtypes ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Notch signaling protects CD4 T cells from STING-mediated apoptosis during acute systemic inflammation

et al. 2020

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Dysregulation of T cell apoptosis contributes to the pathogenesis of acute systemic inflammation–induced immunosuppression, as seen in sepsis and trauma. However, the regulatory mechanisms of T cell apoptosis are unclear. Activation of stimulator of interferon genes (STING) has been shown to induce T cell apoptosis. Notch was previously identified as the top negative regulator of STING in macrophages through a kinase inhibitor library screening. However, how Notch signaling regulates STING activation in T cells is unknown. Here, using a γ-secretase inhibitor to block Notch signaling, we found that Notch protected CD4 T cells from STING-mediated apoptosis during endotoxemia. Mechanistically, Notch intracellular domain (NICD) interacted with STING at the cyclic dinucleotide (CDN) binding domain and competed with CDN to inhibit STING activation. In conclusion, our data reveal a previously unidentified role of Notch in negative regulation of STING-mediated apoptosis in CD4 T cells.

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“…According to the results obtained so far, the combination of a GSI and glucocorticoids in T-ALL therapy may have increased efficacy and decreased toxicity [22]. Moreover, the use of a GSI together with conventional chemotherapy resulted in potentiated drug-induced cell death in B-ALL cells by upregulating intracellular levels of reactive oxygen species [23].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive chromosomal aberrations in a case of a patient with TCF3-HLF-positive BCP-ALL

et al. 2020

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Background: The use of high-throughput analytical techniques has enabled the description of acute lymphoblastic leukaemia (ALL) subtypes. The TCF3-HLF translocation is a very rare rearrangement in ALL that is associated with an extremely poor prognosis. The TCF3-HLF fusion gene in the described case resulted in the fusion of the homeoboxrelated gene of TCF3 to the leucine zipper domain of HLF. The TCF3-HLF fusion gene product acts as a transcriptional factor leading to the dedifferentiation of mature B lymphocytes into an immature state (lymphoid stem cells). This process initiates the formation of pre-leukaemic cells. Due to the rarity of this chromosomal aberration, only a few cases have been described in the literature. The advantage of this work is the presentation of an interesting case of clonal evolution of cancer cells and the cumulative implications (diagnostic and prognostic) of the patient's genetic alterations. Case presentation: This work presents a patient with diagnosed with TCF3-HLF-positive ALL. Moreover, the additional genetic alterations, which play a key role in the pathogenesis of ALL, were detected in this patient: deletion of a fragment from the long arm of chromosome 13 (13q12.2-q21.1) containing the RB1 gene, intragenic deletions within the PAX5 gene and NOTCH1 intragenic duplication. Conclusions: A patient with coexistence of chromosomal alterations and the TCF3-HLF fusion has not yet been described. Identifying all these chromosomal aberrations at the time of diagnosis could be sufficient to determine the cumulative effects of the described deletions on the activity of other oncogenes or tumour suppressors, as well as on the clinical course of the disease. On the other hand, complex changes in the patient's karyotype and clonal evolution of cancer cells call into question the effectiveness of experimental therapy.

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Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia

Cited by 35 publications

References 46 publications

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia

Notch signaling protects CD4 T cells from STING-mediated apoptosis during acute systemic inflammation

Comprehensive chromosomal aberrations in a case of a patient with TCF3-HLF-positive BCP-ALL

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