Article

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.

Creador

• 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.
• Fang, J.

Licencia

• All rights reserved

Presentador

Jose Cancelas

Colegio

• Medicine

Departamento

• Hoxworth Blood Center

Fecha de creacion

• 2014-09

Editor

• Cell Reports

Título de la revista

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

Nota

• This work was part of a pilot "mediated-deposit model" where library staff found potential works, later submitted for faculty review

Elementos

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