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  • Myeloid Malignancies with Chromosome 5q Deletions Acquire a Dependency on an Intrachromosomal NF-kB Gene Network

    Article thumbnail: Myeloid Malignancies with Chromosome 5q Deletions Acquire a Dependency on an Intrachromosomal NF-kB Gene Network
    Type:
    Article
    Description/Abstract:
    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-kB 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-kB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-kB 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-kB to sustain TRAF6/NF-kB 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.
    Creator/Author:
    Komurov, K.; Maciejewski, J. P.; Bolanos, L.; Grimes, H. L.; Cancelas, Jose A.; Chen, X.; Barker, B.; Weirauch, M. T.; Jerez, A.; Liu, X.; Makishima, H.; Christie, S.; Starczynowski, D. T.; Rao, D. S., and Fang, J.
    Submitter:
    Jose Cancelas
    Date Uploaded:
    02/08/2017
    Date Modified:
    04/10/2017
    Date Created:
    2014-09
    License:
    All rights reserved