MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy

Kojima, Kensuke; Konopleva, Marina; Samudio, Ismael; Shikami, Masato; Cabreira-Hansen, Maria da Graça; McQueen, Teresa; Ruvolo, Vivian; Tsao, Twee; Zeng, Zhihong; Vassilev, Lyubomir T.; Andreeff, Michael

doi:10.1182/blood-2005-02-0553

Cited by 353 publications

(444 citation statements)

References 55 publications

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“…The proportion of Annexin V positive cells was also markedly increased by Nultin-3 in those cells showing a high Caspase-3/7 activity, but not in other cells (Supplementary Figure 1A). In agreement with previous reports that leukemia cells are sensitive to p53-induced apoptosis (Kojima et al, 2005;Stuhmer et al, 2005;Secchiero et al, 2006), all leukemia cell lines that we tested underwent apoptosis ( Figure 1a). Next, we investigated whether the apoptotic response induced by Nutlin-3 correlated with its antitumor response.…”

Section: Resultssupporting

confidence: 80%

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

et al. 2008

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Section: Resultssupporting

confidence: 80%

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

et al. 2008

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“…(B) In contrast, full-length wild-type p53 was expressed at low levels (53-kDa band) and with a consistent 2D pattern in PBMCs from healthy donors. 27,28 Equivalent results were obtained for both cell types. In resting Molm-13 and LNCaP cells, full-length p53 and ⌬p53 isoforms were detected at the same pI as in normal PBMCs and AML blast cells.…”

Section: P63 Phosphorylated P53 Full-length P53 and ⌬P53 Isoforms mentioning

confidence: 67%

Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53

Irish

Ånensen

Hovland

et al. 2006

Blood

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Loss or mutation of the TP53 tumor suppressor gene is not commonly observed in acute myeloid leukemia (AML), suggesting that there is an alternate route for cell transformation. We investigated the hypothesis that previously observed Bcl-2 family member overexpression suppresses wild-type p53 activity in AML. We demonstrate that wild-type p53 protein is expressed in primary leukemic blasts from patients with de novo AML using 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and phospho-specific flow cytometry. We found that p53 was heterogeneously expressed and phosphorylated in AML patient samples and could accumulate following DNA damage. Overexpression of antiapoptosis protein Bcl-2 in AML cells was directly correlated with p53 expression and phosphorylation on serine residues 15, 46, and 392. Within those patients with the highest levels of Bcl-2 expression, we identified a mutation in FLT3 that duplicated phosphorylation site Y591. The presence of this mutation correlated with greater than normal IntroductionWe have previously reported that signaling profiles of acute myeloid leukemia (AML) cells identify patients with a poor response to course one of chemotherapy. 1 In that study we showed that mutation of fms-like tyrosine kinase 3 (Flt3) was associated with increased activity of signal transduction and activator of transcription (STAT) family members Stat5 and Stat3, but we did not explore how this signaling might contribute to the observed therapy resistance. Here we examine the connection between a target of altered Stat5 signaling in AML-the Bcl-2 protein-and the suppression of normal apoptotic responses to DNA damage in leukemia cells. Evasion of apoptosis contributes to the formation and continued survival of cancer cells 2 and insight into signaling mechanisms that suppress apoptosis in AML cells could be used to improve the efficacy of existing therapies. 3 AML is particularly relevant to the study of suppressed apoptotic pathways in cancer because p53, a central driver of apoptosis and guardian of genomic integrity, is not generally lost or mutated in this disease. 4,5 p53 is a sequence-specific transcription factor that can halt progression through the cell cycle or initiate apoptosis. 6 Furthermore, p53 is a key tumor suppressor protein often lost or mutated in human cancers; however, TP53 has been reported to be mutant in only 7% of AML cases. 4 Subsequent research has also shown that downstream p53 effector genes, such as p21, are rarely lost in AML and that wild-type p53 protein is expressed in newly established AML derived cell lines. 7 For this study, we measured several properties of p53 in primary AML cells, including TP53 gene sequence, per-cell abundance of p53 protein, and p53 phosphorylation at 5 residues. 8 Following DNA damage and cell stresses, p53 protein is rapidly phosphorylated at several residues, 9 including those we measured here (serines 15, 20, 37, 46, and 392). Phosphorylation of p53 is thought to regulate p53 localization, conformation, and activity, 10 but t...

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“…As described before, Nutlin-3 is a non-genotoxic activator of p53 that bypasses the need for stress-induced signaling by directly blocking MDM2 binding to p53 (Vassilev et al, 2004). Importantly, Nutlin-3 triggers p53-dependent apoptosis in some cell types without inducing p53 phosphorylation (Thompson et al, 2004;Vassilev et al, 2004;Kojima et al, 2005;Tovar et al, 2006). In their comparison of cells treated with DNA damaging agents versus Nutlin-3, Thompson et al (2004) demonstrated that phosphorylation of Ser6, -15, -20, -37, -46 and -392 are dispensable for p53-dependent apoptosis.…”

Section: The Hematopoietic Zinc-finger Cofactormentioning

confidence: 82%

Mechanisms of regulatory diversity within the p53 transcriptional network

2008

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MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy

Cited by 353 publications

References 55 publications

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53

Mechanisms of regulatory diversity within the p53 transcriptional network

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