MERIT40 deficiency expands hematopoietic stem cell pools by regulating thrombopoietin receptor signaling

Rozenova, Krasimira; Jiang, Jing; Donaghy, Ryan; Aressy, Bernadette; Greenberg, Roger A.; Tong, Wei

doi:10.1182/blood-2014-07-588145

Cited by 8 publications

(16 citation statements)

References 67 publications

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“…S1A), as recently described (Rozenova et al 2015). Decreased transcript level of MERIT40 mRNA was detected across seven exons by RT-PCR (data not shown), and MERIT40 protein was undetectable in Merit40 −/− mouse embryonic fibroblasts (MEFs), as determined by Western blotting (Supplemental Fig.…”

Section: Merit40mentioning

confidence: 84%

“…S1B). Merit40 −/− mice were viable and fertile and did not display overt phenotypes in the absence of exogenous genotoxic stress (Rozenova et al 2015; this study). However, as predicted by prior studies Shao et al 2009;Wang et al 2009), Merit40 −/− MEFs displayed reduced protein levels of binding partners and proliferative rates, impaired G2/M checkpoint function, and loss of BRCA1 and RAP80 foci after ionizing radiation (IR) (Fig.…”

Section: Merit40mentioning

confidence: 99%

“…The MERIT40 locus was disrupted by insertion of the Omnibank gene trap vector 76 into the MERIT40 first intron upstream of exon 2 containing the ATG translation start site as described in Rozenova et al (2015) and on the Texas A&M Institute for Genomic Medicine Web site (http://www.tigm.org). Chimeric mice were generated and bred to B6(Cg)-Tyr…”

Section: C-2jmentioning

confidence: 99%

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MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

et al. 2015

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MERIT40 is an essential component of the RAP80 ubiquitin recognition complex that targets BRCA1 to DNA damage sites. Although this complex is required for BRCA1 foci formation, its physiologic role in DNA repair has remained enigmatic, as has its relationship to canonical DNA repair mechanisms. Surprisingly, we found that Merit40 −/− mice displayed marked hypersensitivity to DNA interstrand cross-links (ICLs) but not whole-body irradiation. MERIT40 was rapidly recruited to ICL lesions prior to FANCD2, and Merit40-null cells exhibited delayed ICL unhooking coupled with reduced end resection and homologous recombination at ICL damage. Interestingly, Merit40 mutation exacerbated ICL-induced chromosome instability in the context of concomitant Brca2 deficiency but not in conjunction with Fancd2 mutation. These findings implicate MERIT40 in the earliest stages of ICL repair and define specific functional interactions between RAP80 complex-dependent ubiquitin recognition and the Fanconi anemia (FA)-BRCA ICL repair network.

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Section: Merit40mentioning

confidence: 84%

Section: Merit40mentioning

confidence: 99%

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MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

et al. 2015

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“…The candidates were chosen from the literature based on the following criteria: (1) the knockout increased the repopulating capacity of HSCs, (2) the knockout enhanced HSC frequency and self-renewal, and (3) the knockout did not cause tumorigenesis in serial transplantations. Based on these criteria, we chose 10 candidate genes, namely Lnk [ 21 , 28 , 29 ], p18Ink4c ( p18 ) [ 30 , 31 ], Mapk14 ( p38 ) [ 32 ], Egr1 [ 33 ], Ikkb [ 34 ], p190-B ( p190 ) [ 35 ], Merit40 ( M40 ) [ 36 , 37 , 38 ], Gli1 [ 39 ], c-Cbl ( Cbl ) [ 20 ], and GzmB [ 40 ]. Prior to the screen, each sgRNA of the library was independently tested in a fluorescent reporter assay for on-target cleavage activity ( Figure S1a–c ).…”

Section: Resultsmentioning

confidence: 99%

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

Klatt

Schinke

et al. 2020

Cells

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Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy.

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“…Mutations which enhance MPL signaling result in superior hematopoietic stem cell reconstitution ability and self-renewal in mouse models. This includes mice deficient in negative regulators of MPL signaling such as Lnk [ 23 ] and MERIT-40 [ 24 ].…”

Section: Thrombopoietin/mpl Signaling Pathway In Hsc Quiescence Anmentioning

confidence: 99%

Inflammation as a Driver of Clonal Evolution in Myeloproliferative Neoplasm

Fleischman

2015

Mediators of Inflammation

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Our understanding of inflammation's role in the pathogenesis of myeloproliferative neoplasm (MPN) is evolving. The impact of chronic inflammation, a characteristic feature of MPN, likely goes far beyond its role as a driver of constitutional symptoms. An inflammatory response to the neoplastic clone may be responsible for some pathologic aspects of MPN. Moreover, JAK2V617F mutated hematopoietic stem and progenitor cells are resistant to inflammation, and this gives the neoplastic clone a selective advantage allowing for its clonal expansion. Because inflammation plays a central role in MPN inflammation is a logical therapeutic target in MPN.

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MERIT40 deficiency expands hematopoietic stem cell pools by regulating thrombopoietin receptor signaling

Abstract: • MERIT40-deficient mice harbor an expanded HSC pool with increased quiescence, enhanced self-renewal, and reconstitution potential.• MERIT40 negatively controls HSC homeostasis through regulating the Tpo/Mpl pathway.

Cited by 8 publications

References 67 publications

MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

Inflammation as a Driver of Clonal Evolution in Myeloproliferative Neoplasm

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