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.
Severe congenital neutropenia (SCN) is often associated with inherited heterozygous point mutations in ELANE, which
encodes neutrophil elastase (NE). However, a lack of appropriate models to recapitulate SCN has substantially hampered
the understanding of the genetic etiology and pathobiology of this disease. To this end, we generated both normal and SCN
patient–derived induced pluripotent stem cells (iPSCs), and performed genome editing and differentiation protocols that
recapitulate the major features of granulopoiesis. Pathogenesis of ELANE point mutations was the result of promyelocyte
death and differentiation arrest, and was associated with NE mislocalization and activation of the unfolded protein
response/ER stress (UPR/ER stress). Similarly, high-dose G-CSF (or downstream signaling through AKT/BCL2) rescues
the dysgranulopoietic defect in SCN patient–derived iPSCs through C/EBPβ-dependent emergency granulopoiesis. In
contrast, sivelestat, an NE-specific small-molecule inhibitor, corrected dysgranulopoiesis by restoring normal intracellular
NE localization in primary granules; ameliorating UPR/ER stress; increasing expression of CEBPA, but not CEBPB; and
promoting promyelocyte survival and differentiation. Together, these data suggest that SCN disease pathogenesis includes
NE mislocalization, which in turn triggers dysfunctional survival signaling and UPR/ER stress. This paradigm has the
potential to be clinically exploited to achieve therapeutic responses using lower doses of G-CSF combined with targeting to
correct NE mislocalization.
A raw dataset produced using the clot on a suture experimental set up in the Holland lab (previously published in Bader 2015 & other articles). Data gathered and further analyzed using MATLAB 2012b.
A raw dataset produced using the clot on a suture experimental set up in the Holland lab (previously published in Bader 2015 & other articles). Data gathered and further analyzed using MATLAB 2012b.
A raw dataset produced using the clot on a suture experimental set up in the Holland lab (previously published in Bader 2015 & other articles). Data gathered and further analyzed using MATLAB 2012b.
A raw dataset produced using the clot on a suture experimental set up in the Holland lab (previously published in Bader 2015 & other articles). Data gathered and further analyzed using MATLAB 2012b.
A raw dataset produced using the clot on a suture experimental set up in the Holland lab (previously published in Bader 2015 & other articles). Data gathered and further analyzed using MATLAB 2012b.
