Molecular mechanisms of TP53 dysfunction in lymphoid malignancies
| Levels . | Dysregulation . | Effect . | Occurrence or examples . |
|---|---|---|---|
| DNA | CDS mutations | Loss of function and gain of function | 14.9% occurrence in lymphoid/plasmacytic malignancies |
| Polymorphisms | Different function and stability | p53Pro72 associated with increased lymphoma risk | |
| Promoter mutations | Decreased gene expression | Rare | |
| Promoter and UTR methylations | Gene silencing | 32% in ALL (8 of 25 patients) | |
| 19% in CLL (10 of 54 patients) | |||
| 4% in DLBCL (4 of 108 patients) | |||
| Transcriptional repressors | Decreased transcription | PAX-5 overexpressed in LPL | |
| OM from active T lymphocytes and macrophages | |||
| LANA in PEL | |||
| UTR mutations | Reduced translation efficiency | Single-nucleotide substitution in ALL | |
| RNA | Alternative splicing | Selective TA function | |
| Loss of TA function | |||
| May be related to chemotherapy response | Δp53 probably p53β in AML | ||
| Truncated p53 (50 kDa) in PW B-cell lymphoma cells with BSO treatment | |||
| Selective TA function | p53β, p53γ | ||
| Loss of function; stabilizes p53 | Δ40p53 | ||
| Inhibit p53 function | Δ133p53α, Δ133p53γ | ||
| Alternative internal ribosome entry site | Δ40p53 in H1299 cells | ||
| Translation efficiency | MDM2 impacts p53 translation and levels in H1299 cells | ||
| Suppressed translation by miRNAs | miR-15a and miR-16-1 in CLL | ||
| miR-25 and miR-30d in MM cells | |||
| miR-125b in H1299 cells | |||
| Protein | Stability | p53 degradation | MTBP, TRIM28, TAF1, YY1, and p300 enhance MDM2-mediated degradation of p53 in H1299 or lymphoma cells |
| INK4/ARF proteolysis in BL cells | |||
| Gene silencing of p16 in BL cells | |||
| Functional inhibition of p53 TA | Loss of ASPP1 in ALL | ||
| Inhibition by MIF in mouse models | |||
| Inhibition by MDMX, PLK1, YY1, DJ-1, and APAK in H1299 | |||
| Decreased activation | Post-translational modifications | ||
| ATM inactivation in CLL | |||
| Localization regulation |
| Levels . | Dysregulation . | Effect . | Occurrence or examples . |
|---|---|---|---|
| DNA | CDS mutations | Loss of function and gain of function | 14.9% occurrence in lymphoid/plasmacytic malignancies |
| Polymorphisms | Different function and stability | p53Pro72 associated with increased lymphoma risk | |
| Promoter mutations | Decreased gene expression | Rare | |
| Promoter and UTR methylations | Gene silencing | 32% in ALL (8 of 25 patients) | |
| 19% in CLL (10 of 54 patients) | |||
| 4% in DLBCL (4 of 108 patients) | |||
| Transcriptional repressors | Decreased transcription | PAX-5 overexpressed in LPL | |
| OM from active T lymphocytes and macrophages | |||
| LANA in PEL | |||
| UTR mutations | Reduced translation efficiency | Single-nucleotide substitution in ALL | |
| RNA | Alternative splicing | Selective TA function | |
| Loss of TA function | |||
| May be related to chemotherapy response | Δp53 probably p53β in AML | ||
| Truncated p53 (50 kDa) in PW B-cell lymphoma cells with BSO treatment | |||
| Selective TA function | p53β, p53γ | ||
| Loss of function; stabilizes p53 | Δ40p53 | ||
| Inhibit p53 function | Δ133p53α, Δ133p53γ | ||
| Alternative internal ribosome entry site | Δ40p53 in H1299 cells | ||
| Translation efficiency | MDM2 impacts p53 translation and levels in H1299 cells | ||
| Suppressed translation by miRNAs | miR-15a and miR-16-1 in CLL | ||
| miR-25 and miR-30d in MM cells | |||
| miR-125b in H1299 cells | |||
| Protein | Stability | p53 degradation | MTBP, TRIM28, TAF1, YY1, and p300 enhance MDM2-mediated degradation of p53 in H1299 or lymphoma cells |
| INK4/ARF proteolysis in BL cells | |||
| Gene silencing of p16 in BL cells | |||
| Functional inhibition of p53 TA | Loss of ASPP1 in ALL | ||
| Inhibition by MIF in mouse models | |||
| Inhibition by MDMX, PLK1, YY1, DJ-1, and APAK in H1299 | |||
| Decreased activation | Post-translational modifications | ||
| ATM inactivation in CLL | |||
| Localization regulation |
LPL indicates lymphoplasmacytic lymphoma; OM, oncostatin M; LANA, latency-associated nuclear antigen; PEL, primary effusion lymphoma; and BSO, L-buthionine sulfoximine.