These results support the role of aberrant chromatin accessibility and consequent oncogenic <i>MYC</i> enhancer activation in NOTCH1-induced T-ALL.<i>This article is highlighted in the In This Issue feature, p. 1631</i>.
Here we studied the phenotype of Per LAMs, their subpopulations in Notch1-induced acute lymphoblastic leukemia mice and compared with LAMs from BM or spleen in the same model.
Systematic interactome mapping of acute lymphoblastic leukemia cancer gene products reveals EXT-1 tumor suppressor as a Notch1 and FBWX7 common interactor.
Forty-two somatic Notch1 mutations, including 7 nonsense mutations and 11 mutations within the domain commonly harboring potential activating mutations in acute lymphoblastic leukemia, were detected in 22 (43%) of the 51 Chinese OSCC tumors.
Mechanistically, loss of SH2B3 increases Janus kinase-signal transducer and activator of transcription signaling, promotes lymphoid cell proliferation, and accelerates leukemia development in a mouse model of NOTCH1-induced ALL.
Two T-lymphoblastic leukemia (T-ALL) cell lines and two acute myeloblastic leukemia (AML) cell lines were transfected with siRNAs targeting NOTCH1 and NOTCH2.
Interestingly, gain-of-function mutations or cryptic transcription initiation of the Notch1 gene have been frequently found in both human and mouse T-ALL.
Moreover, expression of Notch1, an essential gene for developing hematological cells and T-ALL, was found to be negatively correlated with β-arrestin1 in ALL.
To further investigate the molecular mechanisms underlying proliferation suppression and apoptosis and explore effective downstream target genes, we used RNA interference (RNAi) technology to down-regulate the expression of Notch-1 in GSIs-resistant T-ALL cell lines.
Here we have investigated the prognostic impact of mutations in the NOTCH1 pathway, in particular, the NOTCH1 and FBXW7 genes, in a large cohort of adult patients with T-lymphoblastic leukemia (n=126).
Using parallel studies in T cell progenitors and established T-ALL lines we have demonstrated that the NFkappaB signaling pathway is targeted and induced by Notch1 activation.
These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs.
NOTCH1 pathway activation represents a common feature of T-ALL when compared to acute myelogenous leukemia (AML) and B-cell precursor acute lymphoblastic leukemia.