| First Author | Volk A | Year | 2014 |
| Journal | J Exp Med | Volume | 211 |
| Issue | 6 | Pages | 1093-108 |
| PubMed ID | 24842373 | Mgi Jnum | J:213732 |
| Mgi Id | MGI:5585683 | Doi | 10.1084/jem.20130990 |
| Citation | Volk A, et al. (2014) Co-inhibition of NF-kappaB and JNK is synergistic in TNF-expressing human AML. J Exp Med 211(6):1093-108 |
| abstractText | Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor kappaB (NF-kappaB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-kappaB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-kappaB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor alpha (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK-AP1 pathway in a manner parallel to NF-kappaB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-kappaB inhibitor treatment by blocking the TNF-JNK-AP1 signaling pathway. Our data suggest that co-inhibition of both TNF-JNK-AP1 and NF-kappaB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC. |
