Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

Perugini, Michelle; Kok, Chung Hoow; Brown, Anna L.; Wilkinson, Christopher; Salerno, Diana; Young, Sonia M.; Diakiw, Sonya M.; Lewis, ID; Gonda, Thomas J.; D’Andrea, Richard J.

doi:10.1038/leu.2008.349

Cited by 22 publications

(19 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To examine whether the impaired colony-forming ability of 32D-RUNX1dC cells attributed to the repressed expression of Gadd45a by RUNX1dC, we introduced the expression vector for Gadd45a into 32D-RUNX1dC cells, which was named 32D-RUNX1dC-Gadd45a (Supplementary Figure 3a). Consistent with the report from Perugini et al, 27 Gadd45a overexpression reduced the cell proliferation ability at steady state (Figure 4a Figure 3b). Furthermore, we found exogenously expressed Gadd45a reduced gH2AX-positive foci in 32D-RUNX1dC-Gadd45a cl1 cells compared with 32D-RUNX1dC-GFP cells after UV-B treatment (Figure 4b).…”

Section: Runx1dc Suppresses Gadd45a Expression In Lsk Cellssupporting

confidence: 82%

“…31 The similar phenotypes of Gadd45a þ /À and RUNX1 þ /À mice raise the possibility that both molecules have closely related roles in maintaining genome stability. As for the relationship between RUNX1 and Gadd45a, Perugini et al 27 recently reported that GADD45A expression was significantly downregulated in RUNX1-ETO-positive AML cells compared with normal controls. Although they demonstrated ERK1/2 signaling was involved in the repression of GADD45A in several AML cell lines, its mechanism was not analyzed in their study.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

et al. 2011

View full text Add to dashboard Cite

Loss-of-function mutations of RUNX1 have been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Although several reports have suggested roles for RUNX1 as a tumor suppressor, its precise function remains unknown. Because gene alterations of RUNX1 by themselves do not lead to the development of leukemia in mouse models, additional mutation(s) would be required for leukemia development. Here, we report that the C-terminal deletion mutant of RUNX1, RUNX1dC, attenuates DNA-damage repair responses in hematopoietic stem/progenitor cells. cH2AX foci, which indicate the presence of DNA double-strand breaks, were more abundantly accumulated in RUNX1dC-transduced lineage À Sca1 þ c-kit þ (LSK) cells than in mock-transduced LSK cells both in a steady state and after c-ray treatment. Expression profiling by real-time -PCR array revealed RUNX1dC represses the expression of Gadd45a, a sensor of DNA stress. Furthermore, bone marrow cells from MDS/AML patients harboring the RUNX1-C-terminal mutation showed significantly lower levels of GADD45A expression compared with those from MDS/AML patients with wild-type RUNX1. As for this mechanism, we found that RUNX1 directly regulates the transcription of GADD45A and that RUNX1 and p53 synergistically activate the GADD45A transcription. Together, these results suggest Gadd45a dysfunction due to RUNX1 mutations can cause additional mutation(s) required for multi-step leukemogenesis.

show abstract

Section: Runx1dc Suppresses Gadd45a Expression In Lsk Cellssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Gadd45a was primarily considered as a pro-apoptotic gene, and has been reported as being able to activate the mitochondrial pathway of apoptosis [26] . It has been reported that knockdown of Gadd45a led to increased growth and survival of FDB1 myeloid cells [27] . Moreover, Zhang et al found that high level expression of Gadd45a sensitized M1 myeloblastic leukemia and H1299 lung carcinoma cell lines to apoptosis induced by gamma-irradiation [28] .…”

Section: Discussionmentioning

confidence: 99%

Over-expression of Gadd45a enhances radiotherapy efficacy in human Tca8113 cell line

Zhang

Wang

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim:To investigate the effect of the growth arrest-and DNA damage-inducible Gadd45a gene on the radiosensitivity of human tongue squamous cell carcinoma cell line to ionizing radiation (IR). Methods: Short interfering ribonucleic acid (si-RNA) targeting Gadd45a or an irrelevant mRNA (nonsense si-RNA) was chemically synthesized. The constructed si-RNAs were transfected into Tca8113 cells and Gadd45a expression was determined using quantitative real-time PCR and Western-blot. After 24-h exposure to IR at a dose rate of 4 Gy/min, apoptosis of Tca8113 cells was detected using flow cytometry, and radiosensitivity was measured using MTT assays. Results: IR apparently increased the expression of Gadd45a at mRNA and protein levels in Tca8113 cells. The effect was efficiently inhibited by transfection with Gadd45a si-RNA (P<0.01). Furthermore, silencing Gadd45a gene significantly increased cell viability and decreased the percentage of apoptotic cells during irradiation, which indicated that IR-induced Gadd45a over-expression could increase the radiosensitivity of Tca8113 cells. Conclusion: These results indicated that targeting Gadd45a may have important therapeutic implications in sensitizing Tca8113 cells to IR.

show abstract

“…TC252 GADD45A-overexpressing cells were generated using retroviral spin-infection as previously described (21).…”

Section: Gadd45a Overexpressionmentioning

confidence: 99%

Nutlin-3a Efficacy in Sarcoma Predicted by Transcriptomic and Epigenetic Profiling

et al. 2014

View full text Add to dashboard Cite

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n ¼ 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists. Cancer Res; 74(3); 921-31. Ó2013 AACR.

show abstract

Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

Cited by 22 publications

References 49 publications

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

C-terminal mutation of RUNX1 attenuates the DNA-damage repair response in hematopoietic stem cells

Over-expression of Gadd45a enhances radiotherapy efficacy in human Tca8113 cell line

Nutlin-3a Efficacy in Sarcoma Predicted by Transcriptomic and Epigenetic Profiling

Contact Info

Product

Resources

About