Cell Reports
Volume 8, Issue 5, 11 September 2014, Pages 1328-1338
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Myeloid Malignancies with Chromosome 5q Deletions Acquire a Dependency on an Intrachromosomal NF-κB Gene Network

https://doi.org/10.1016/j.celrep.2014.07.062Get rights and content
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Highlights

  • Deletion of miR-146a is a driving molecular event in del(5q) MDS/AML

  • NF-κB induces expression of p62, a haploid 5q gene, in miR-146a-deficient MDS/AML

  • p62 is necessary for leukemic cells by sustaining TRAF6/NF-κB signaling

  • Blocking p62/TRAF6 binding is a potential therapeutic approach in del(5q) MDS/AML

Summary

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-κB activation. Increased survival and proliferation of HSPCs from miR-146alow 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-κB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-κB 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-κB to sustain TRAF6/NF-κB 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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).