Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice

Herold, Marco J.; Stuchbery, Ryan; Mérino, Delphine; Willson, Tracy A.; Strasser, Andreas; Hildeman, David A.; Bouillet, Philippe

doi:10.1038/cddis.2014.409

Cited by 28 publications

(28 citation statements)

References 29 publications

(41 reference statements)

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“…To establish the role of CHK1 in adult hematopoiesis, we aimed to conditionally delete Chk1 in adult mice by taking advantage of tamoxifen (TAM)‐inducible and hematopoiesis‐restricted Cre transgene expression in Vav‐Cre ERT2 mice . To monitor recombination in hematopoietic cells by flow cytometry, we additionally introduced a CRE‐reporter allele (mT/mG) in the ROSA26 locus that enables expression of membrane‐targeted Tomato prior to and membrane‐targeted GFP after CRE‐mediated excision of a loxP flanked STOP cassette .…”

Section: Resultsmentioning

confidence: 99%

Checkpoint kinase 1 is essential for fetal and adult hematopoiesis

et al. 2019

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Checkpoint kinase 1 (CHK1) is critical for S‐phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumor cells have developed a strong dependence on CHK1 for survival, and hence, this kinase has developed into a promising drug target. Chk1 deficiency in mice results in blastocyst death due to G2/M checkpoint failure showing that it is an essential gene and may be difficult to target therapeutically. Here, we show that chemical inhibition of CHK1 kills murine and human hematopoietic stem and progenitor cells (HSPCs) by the induction of BCL2‐regulated apoptosis. Cell death in HSPCs is independent of p53 but requires the BH3‐only proteins BIM, PUMA, and NOXA. Moreover, Chk1 is essential for definitive hematopoiesis in the embryo. Noteworthy, cell death inhibition in HSPCs cannot restore blood cell formation as HSPCs lacking CHK1 accumulate DNA damage and stop dividing. Moreover, conditional deletion of Chk1 in hematopoietic cells of adult mice selects for blood cells retaining CHK1, suggesting an essential role in maintaining functional hematopoiesis. Our findings establish a previously unrecognized role for CHK1 in establishing and maintaining hematopoiesis.

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Section: Resultsmentioning

confidence: 99%

Checkpoint kinase 1 is essential for fetal and adult hematopoiesis

et al. 2019

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“…We further examined whether early embryonic hematopoietic cells can contribute to pericyte development. Using a tamoxifen-induced Vav-Cre ER driver (Herold et al, 2014), we induced EYFP expression in Vav-Cre ER ;R26R EYFP embryos at E8.5~E10.5, the stages prior to dermal development. EYFP + tissue-localized myeloid cells were observed in E16.5 Vav-Cre ER ;R26R EYFP skin (Figures 3A and 3B).…”

Section: Resultsmentioning

confidence: 99%

“…C57BL/6 mice (The Jackson Laboratory), Wnt1-Cre mice (Danielian et al, 1998), Tie2-Cre mice (Kisanuki et al, 2001), Cdh5-BAC-Cre ERT2 mice (Okabe et al, 2014), Vav-iCre mice (The Jackson laboratory, (Georgiades et al, 2002), Vav-Cre ER mice (Herold et al, 2014), CD11b-Cre mice (Boillee et al, 2006), Csf1r-iCre mice (The Jackson laboratory, (Deng et al, 2010), Csf1r-MER-iCre-MER mice (The Jackson laboratory, (Qian et al, 2011), LysM-Cre mice (The Jackson laboratory, (Clausen et al, 1999), WT1-Cre mice (Wessels et al, 2012) , R26R (The Jackson laboratory, (Soriano, 1999), R26R EYFP mice (The Jackson laboratory, (Srinivas et al, 2001), Ai14 mice (The Jackson laboratory, (Madisen et al, 2010), PU.1 −/− mice (Scott et al, 1994), Csf1 op/op mice (The Jackson laboratory, (Yoshida et al, 1990) and Tgfbr2 flox mice (The Jackson laboratory, (Leveen et al, 2002) have been reported elsewhere. All experiments were carried out according to the guidelines approved by the National Heart, Lung, and Blood Institute Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

Tissue Myeloid Progenitors Differentiate into Pericytes through TGF-β Signaling in Developing Skin Vasculature

et al. 2017

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SUMMARY Mural cells (pericytes and vascular smooth muscle cells) are essential for the regulation of vascular networks and maintenance of vascular integrity, but their origins are diverse in different tissues and not known in the organs that arise from the ectoderm, such as skin. Here we show that tissue-localized myeloid progenitors contribute to pericyte development in embryonic skin vasculature. A series of in vivo fate-mapping experiments indicates that tissue myeloid progenitors differentiate into pericytes. Furthermore, depletion of tissue myeloid cells and their progenitors in PU.1 mutants results in defective pericyte development. FACS-isolated myeloid cells and their progenitors from embryonic skin differentiate into pericytes in culture. At the molecular level, transforming growth factor-β (TGF-β) induces pericyte differentiation in culture. Furthermore, type2 TGF-β receptor (Tgfbr2) mutants exhibit deficient pericyte development in skin vasculature. Combined, these data suggest that pericytes differentiate from tissue myeloid progenitors in the skin vasculature through TGF-β signaling.

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“…BIM is considered the master regulator of immune cell homeostasis. Bim deletion causes increased numbers of lymphoid and myeloid cells, defects in thymocyte development, and global lymphocyte resistance to multiple apoptotic stimuli (34, 35). BIM is essential for negative selection of immature T cells in the thymus, and mice lacking BIM have shorter lifespans due to the development of fatal autoimmunity (34, 36).…”

Section: The Role and Potential Targeting Of Bcl-2 Proteins In The Immentioning

confidence: 99%

Killing Two Cells with One Stone: Pharmacologic BCL-2 Family Targeting for Cancer Cell Death and Immune Modulation

et al. 2016

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A crucial component of regulating organismal homeostasis is maintaining proper cell number and eliminating damaged or potentially malignant cells. Apoptosis, or programed cell death, is the mechanism responsible for this equilibrium. The intrinsic apoptotic pathway is also especially important in the development and maintenance of the immune system. Apoptosis is essential for proper positive and negative selection during B- and T-cell development and for efficient contraction of expanded lymphocytes following an immune response. Tight regulation of the apoptotic pathway is critical, as excessive cell death can lead to immunodeficiency while apoptotic resistance can lead to aberrant lymphoproliferation and autoimmune disease. Dysregulation of cell death is implicated in a wide range of hematological malignancies, and targeting various components of the apoptotic machinery in these cases is an attractive chemotherapeutic strategy. A wide array of compounds has been developed with the purpose of reactivating the intrinsic apoptotic pathway. These compounds, termed BH3 mimetics are garnering considerable attention as they gain greater clinical oncologic significance. As their use expands, it will be imperative to understand the effects these compounds have on immune homeostasis. Uncovering their potential immunomodulatory activity may allow for administration of BH3 mimetics for direct tumor cell killing as well as novel therapies for a wide range of immune-based directives. This review will summarize the major proteins involved in the intrinsic apoptotic pathway and define their roles in normal immune development and disease. Clinical and preclinical BH3 mimetics are described within the context of what is currently known about their ability to affect immune function. Prospects for future antitumor immune amplification and immune modulation are then proposed.

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Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice

Cited by 28 publications

References 29 publications

Checkpoint kinase 1 is essential for fetal and adult hematopoiesis

Checkpoint kinase 1 is essential for fetal and adult hematopoiesis

Tissue Myeloid Progenitors Differentiate into Pericytes through TGF-β Signaling in Developing Skin Vasculature

Killing Two Cells with One Stone: Pharmacologic BCL-2 Family Targeting for Cancer Cell Death and Immune Modulation

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