p53 status of newly established acute myeloid leukaemia cell lines

Zheng, Aiping; Castrén, Katariina; Säily, Marjaana; Er, Savolainen; Koistinen, Pirjo; Vähäkangas, Kirsi

doi:10.1038/sj.bjc.6690064

Cited by 24 publications

(18 citation statements)

References 43 publications

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“…It has been reported that both AML2 and AML3 cell lines contain wild-type p53 by nucleotide sequence analysis. 36,37 Anti-actin, -CDK9, -cyclin T1, -p53, -p21, -HDM2 and -NPM antibodies were purchased from Santa Cruz Biotechnology. Anti-Noxa, -Puma and -Survivin antibodies were obtained from Abcam.…”

Section: Methodsmentioning

confidence: 99%

NPMc+ AML cell line shows differential protein expression and lower sensitivity to DNA-damaging and p53-inducing anticancer compounds

Lew

Tan²,

Gurumurthy³

et al. 2011

Cell Cycle

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Section: Methodsmentioning

confidence: 99%

NPMc+ AML cell line shows differential protein expression and lower sensitivity to DNA-damaging and p53-inducing anticancer compounds

Lew

Tan²,

Gurumurthy³

et al. 2011

Cell Cycle

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“…4,18 This was first observed in HL-60 cells that have a major rearrangement of p53 resulting in absence of p53 expression. 19 A number of groups have examined the occurrence of p53 alterations in various series of different types of hematopoietic cell lines derived from AML, 18,[20][21][22] T acute lymphoblastic leukemia (T-ALL), 23,24 B cell precursor-ALL (BCP-ALL), 25,26 B cell non-Hodgkin's lymphoma (B-NHL), [27][28][29] Burkitt's lymphoma 30,31 and myeloma. 32,33 We have undertaken a comprehensive analysis of the frequency of genomic p53 alterations in human malignant hematopoietic cell lines; data reported in the literature and our unpublished data are summarized in Figure 3.…”

Section: Higher Frequency Of P53 Alterations In Cell Lines Than In Prmentioning

confidence: 99%

p53 alterations in human leukemia–lymphoma cell lines: in vitroartifact or prerequisite for cell immortalization?

Drexler

Matsuo

et al. 2000

Leukemia

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Alteration of the p53 gene is one of the most frequent events in human tumorigenesis. The inactivation of p53 tumor suppressor function can be caused by chromosome deletion, gene deletion, or mainly by point mutations. p53 mutations occur moderately often in hematopoietic malignancies. A significantly higher frequency of p53 alterations in cell lines vs primary samples has been observed for all types of malignant hematopoietic cell lines. It has been postulated that p53 gene abnormalities arise in cell lines during in vitro establishment of the culture or prolonged culture; but it is also conceivable that those cases that carry p53 mutations may be more suitable for in vitro establishment as permanent cell lines. We analyzed data on the p53 gene status in a panel of matched primary hematopoietic tumor cells and the respective cell lines derived from this original material. In 85% (53/62) of the pairs of matched primary cells and cell lines, the in vivo and in vitro data were identical (both with p53 wild-type or both with the same p53 mutation). In some instances, serial clinical samples (eg at presentation and relapse) and serial sister cell lines were available. These cases showed that a clinical sample at presentation often had a p53 wild-type configuration whereas the derived cell line and a relapse specimen carried an identical p53 point mutation. These findings suggest that a minor clone, at first undetectable by standard analysis, represents a reservoir for the outgrowth of resistant cells in vivo and also a pool of cells with a growth advantage in vitro, providing a significantly higher chance of immortalization in culture. This was further supported by studies employing mutant allele-specific gene amplifications, a technique which is significantly more sensitive (100-to 1000-fold) than the commonly applied SSCP assay with a sensitivity threshold of about 10% mutated cells within a pool of wild-type cells. Taken together, this analysis confirms the usefulness of human hematopoietic cell lines as in vitro model systems for the study of the biology of hematopoietic malignancies. It further underlines the notion that p53 gene alterations confer a survival advantage to, at least some, malignant cells in vitro and presumably also in vivo; however, it is highly unlikely that a p53 mutation alone would suffice for the immortalization of a cell line in vitro or tumor development in vivo. Leukemia (2000) 14, 198-206.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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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p53 status of newly established acute myeloid leukaemia cell lines

Cited by 24 publications

References 43 publications

NPMc+ AML cell line shows differential protein expression and lower sensitivity to DNA-damaging and p53-inducing anticancer compounds

NPMc+ AML cell line shows differential protein expression and lower sensitivity to DNA-damaging and p53-inducing anticancer compounds

p53 alterations in human leukemia–lymphoma cell lines: in vitroartifact or prerequisite for cell immortalization?

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

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