Wu et al. map an Nf1-Stat3-Arid1b/ b-catenin pathway that initiates
Neurofibromatosis type 1 (Nf1) neurofibromas, using unbiased
insertional mutagenesis screening. Stat3 transcriptionally represses Gsk3b and Arid1b, thereby activating b-catenin in Schwann cell precursors and resulting in neurofibroma initiation and maintenance.
Stat3-mediated modification plays a role in early tumorigenesis.
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.