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

Fang, Jing; Barker, Brenden; Bolanos, Lyndsey; Liu, Xiaona; Jerez, Andrés; Makishima, Hideki; Christie, Susanne; Rothenberg, Marc E.; Rao, Dinesh S.; Grimes, H. Leighton; Komurov, Kakajan; Weirauch, Matthew T.; Cancelas, José A.; Maciejewski, Jaroslaw P.; Starczynowski, Daniel T.

doi:10.1016/j.celrep.2014.07.062

Cited by 60 publications

(57 citation statements)

References 38 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TIFAB expression is reduced by >75% in del(5q) MDS and AML, 2 whereas expression of miR-146a in heterozygous mice is variable and in some cases at/above levels observed in WT cells; 5 therefore, we examined homozygous-deficient mice as this approach better mimics the expression TIFAB and miR-146a in human del(5q) MDS. All recipient mice efficiently engrafted donor BM cells (Supplementary Figures 1c and d).…”

mentioning

confidence: 99%

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

Choi

Bolanos

et al. 2016

Leukemia

View full text Add to dashboard Cite

mentioning

confidence: 99%

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

Choi

Bolanos

et al. 2016

Leukemia

View full text Add to dashboard Cite

“…Increased activation of Toll-like receptor and IL-1 receptor signaling with downstream activation of MAPK and NF-κB pathways is widely reported in MDS, but the mechanistic basis for this activation have mostly been restricted to MDS with deletion of chromosome 5q (Fang et al, 2014, 2017; Starczynowski, 2014; Varney et al, 2015). Our work identifies a mechanism for hyperactivated NF-κB signaling in a wider spectrum of MDS.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

et al. 2018

View full text Add to dashboard Cite

Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.

show abstract

“…3D). The increase in p62 mRNA could be due to either activation of a positive feedback loop involving the nuclear factor erythoroid 2 (NRF2) (25) or activation of NF-κB by inflammatory cytokines (26). …”

Section: Resultsmentioning

confidence: 99%

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

203

182

View full text Add to dashboard Cite

Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

show abstract

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

Cited by 60 publications

References 38 publications

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Contact Info

Product

Resources

About