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 NF?B 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 NF?B via several mechanisms. Thus, pharmacological inhibition of NOTCH1-NF?B 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. NF?B 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 NF?B inhibition in opposite ways depending on whether they were treated with a stress-inducing chemotherapeutic agent or not. Moreover, we found that NOTCH1 enhances NF?B apoptotic function in the stressed cells. The data argue for further studies of NF?B status in T-ALL patients on different treatment protocols and the impact of activating NOTCH1 mutations on treatment response.

SUBMITTER: Riz I 

PROVIDER: S-EPMC3157555 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature