title: Apoptotic role of IKK in T-ALL therapeutic response.
abstract: Despite considerable progress in the treatment of T cell acute lymphoblastic leukemia (T-ALL), it is still the highest risk malignancy among ALL. The outcome of relapsed patients remains dismal. The pro-survival role of NOTCH1 and NFκB in T-ALL is well documented; also, both factors were reported to be predictive of relapse. The NOTCH1 signaling pathway, commonly activated in T-ALL, was shown to enhance the transcriptional function of NFκB via several mechanisms. Thus, pharmacological inhibition of NOTCH1-NFκB signaling was suggested to be incorporated into existing T-ALL treatment protocols. However, conventional chemotherapy is based on activation of various types of stress, such as DNA damage, mitotic perturbations or endoplasmic reticulum overload. NFκB is frequently activated in response to stress and, depending on yet unknown mechanisms, it either protects cells from the drug action or mediates apoptosis. Here, we report that T-ALL cells respond to NFκB inhibition in opposite ways depending on whether they were treated with a stress-inducing chemotherapeutic agent or not. Moreover, we found that NOTCH1 enhances NFκB apoptotic function in the stressed cells. The data argue for further studies of NFκB status in T-ALL patients on different treatment protocols and the impact of activating NOTCH1 mutations on treatment response.
authors: Department of Anatomy and Regenerative Biology, George Washington University, 2300 I Street NW, Washington, DC 20037, USA. anaixr@gwumc.edu
authors: Irene
authors: I
authors: Riz
authors: Lynnsey A
authors: LA
authors: Zweier-Renn
authors: Ian
authors: I
authors: Toma
authors: Teresa S
authors: TS
authors: Hawley
authors: Robert G
authors: RG
authors: Hawley
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011719:Pyrazines / Q000627:therapeutic use; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014750:Vincristine / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D001897:Boronic Acids; C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D051881:Receptor, Notch1; D014750:Vincristine; D000069286:Bortezomib; D005047:Etoposide; D051550:I-kappa B Kinase