DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-Induced Leukemogenesis In Vivo

Takáčová, Sylvia; Slany, Robert K.; Bártková, Jiřina; Stránecký, Viktor; Doležel, Petr; Lužná, Pavla; Bártek, Jiří; Divoký, Vladimír

doi:10.1016/j.ccr.2012.01.021

Cited by 57 publications

(56 citation statements)

References 33 publications

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“…It was reported that inhibition of DNA damage response (DDR) barriers accelerated MLL-rearrangement leukemogenesis. 43 Our GEP reveals that several pathways involved in DDR are affected by expression of MLL-AF4 alone or in conjunction with FLT3-TKD ( Figure 6C). We found a global downregulation of many components associated with DDR signaling pathways such as DNA repair by homologous recombination, nonhomologous endjoining, or ATM signaling (supplemental Figure 2A-C).…”

Section: Flt3 Activation In Mll-af4-expressing Hescs 3871mentioning

confidence: 99%

“…Additionally, it has been reported that DDR is a ratelimiting event for acquisition of stem cell properties in MLLmediated transformation, as experimental inhibition of the DDR barrier accelerated leukemia development. 43 Our GEP reveals a global downregulation of many components associated with DDR master signaling pathways. These GEP data indicate that although FLT3-TKD does not cooperate with MLL-AF4 to transform hESCs or hESC-derived hematopoietic cells, it induces transcriptional modulation of MLL-AF4 target genes in hESCs-derived CD45 1 hematopoietic cells, partially resembling the scenario found by Guenther et al 19 by ChIP-Seq analysis.…”

Section: Cd34mentioning

confidence: 99%

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FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

Bueno

Ayllón

Montes

et al. 2013

Blood

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Section: Flt3 Activation In Mll-af4-expressing Hescs 3871mentioning

confidence: 99%

Section: Cd34mentioning

confidence: 99%

FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

Bueno

Ayllón

Montes

et al. 2013

Blood

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“…62,133 The conditional MLL-ENL mice develop MPD early (within 7 months) and later develop AML. This can be accelerated by treating with caffeine, an inhibitor of ATM and ATR kinases which are part of the fail-safe DNA damage response machinery, 63 thus, demonstrating the importance of GI in the development of disease. Likewise, KI mice with CEBPa mutations develop AML.…”

Section: Mds Mouse Models Of Altered Transcription Factor and Nuclearmentioning

confidence: 99%

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

2012

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Myelodysplastic syndromes represent particularly challenging hematologic malignancies that arise from a large spectrum of genetic events resulting in a disease characterized by a range of different presentations and outcomes. Despite efforts to classify and identify the key genetic events, little improvement has been made in therapies that will increase patient survival. Animal models represent powerful tools to model and study human diseases and are useful pre-clinical platforms. In addition to enforced expression of candidate oncogenes, gene inactivation has allowed the consequences of the genetic effects of human myelodysplastic syndrome to be studied in mice. This review aims to examine the animal models expressing myelodysplastic syndrome-associated genes that are currently available and to highlight the most appropriate model to phenocopy myelodysplastic syndrome disease and its risk of transformation to acute myelogenous leukemia. ©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.069385 ABSTRACTMouse models myelodysplastic syndrome human candidate genes haematologica | 2013; 98 (1) 11 Figure 1. Mouse models to study malignant hematologic disease. Several strategies can be employed to create mouse models of disease. Candidate genes can be introduced into the germline under the control of appropriate promoters to drive expression in certain cell compartments. Knock-out strategies create gene deficient mice, whilst knock-in strategies use the endogenous promoters; but again these tend to be conditional systems requiring specific promoters to determine in which cell the genes are introduced. Transduction of bone marrow and reinfusion is a powerful tool. Xenograft models are theoretically the best if the techniques involved can be improved.

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“…Similarly, cells that instead bypass the senescence programme may potentially induce a secretory response as a result of genomic instability due to unregulated cellular proliferation. DNA damaged-induced pro-inflammatory responses have also been reported in other systems mediated via ATM (Karakasilioti et al 2013;Takacova et al 2012). Thus, although a secretory phenotype is associated with cell senescence, it does not seem to be directly driven by growth arrest and could occur in other biological settings which activate a DDR.…”

Section: Cell Cycle Arrestmentioning

confidence: 96%

Cellular senescence: from growth arrest to immunogenic conversion

Burton

Faragher

2015

AGE

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Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a proinflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, wellestablished triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established Batypical^senescent states that may occur independent of DNA damage.

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DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-Induced Leukemogenesis In Vivo

Cited by 57 publications

References 33 publications

FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

Cellular senescence: from growth arrest to immunogenic conversion

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