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
Background: Acid -glucosidase is trafficked to the lysosome by LIMP-2.
Results: A unique 11-amino acid sequence on acid -glucosidase was critical for its LIMP-2-dependent targeting to the lysosome.
Conclusion: This sequence is essential for oligosaccharide-independent targeting of synthesized acid -glucosidase to the lysosome.
Significance: Modification of this sequence has basic/therapeutic implications for Gaucher disease and its comorbidities (e.g. Parkinson disease).