Search Constraints
Filtering by:
Creator/Author
Grimes, H. L.
Remove constraint Creator/Author: Grimes, H. L.
1 - 2 of 2
Number of results to display per page
Search Results
- Type:
- Article
- Description/Abstract:
- 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.
- Creator/Author:
- 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., and Fang, J.
- Submitter:
- Jose Cancelas
- Date Uploaded:
- 02/08/2017
- Date Modified:
- 04/10/2017
- Date Created:
- 2014-09
- License:
- All rights reserved
- Type:
- Article
- Description/Abstract:
- 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.
- Creator/Author:
- Lutzko, C.; Mehta, P.; Kalfa, T.; Aronow, B. J.; Myers, K.; Grimes, H. L.; Horwitz, M.; Cancelas, Jose A.; Valencia, C. A.; Trump, L., and Nayak, R. C.
- Submitter:
- Jose Cancelas
- Date Uploaded:
- 02/08/2017
- Date Modified:
- 04/10/2017
- Date Created:
- 2015-07
- License:
- All rights reserved