| First Author | Fang J | Year | 2014 |
| Journal | Cell Rep | Volume | 8 |
| Issue | 5 | Pages | 1328-38 |
| PubMed ID | 25199827 | Mgi Jnum | J:277949 |
| Mgi Id | MGI:6274179 | Doi | 10.1016/j.celrep.2014.07.062 |
| Citation | Fang J, et al. (2014) Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-kappaB gene network. Cell Rep 8(5):1328-38 |
| abstractText | Chromosome 5q deletions (del[5q]) are common in high-risk (HR) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR MDS/AML and miR-146a(-/-) hematopoietic stem/progenitor cells (HSPCs) results in TRAF6/NF-kappaB activation. Increased survival and proliferation of HSPCs from miR-146a(low) HR MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-kappaB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-kappaB signaling, as disrupting the p62-TRAF6 signaling complex results in cell-cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-kappaB to sustain TRAF6/NF-kappaB signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML. |
