PRIMA-1MET cytotoxic effect correlates with p53 protein
reduction in TP53-mutated chronic lymphocytic leukemia cells

J 2020

PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells

JAŠKOVÁ, Zuzana, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Yvona BRYCHTOVÁ, Martin TRBUŠEK et. al.

Basic information

Original name

PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells

Authors

JAŠKOVÁ, Zuzana (703 Slovakia, belonging to the institution), Šárka PAVLOVÁ (203 Czech Republic, belonging to the institution), Jitka MALČÍKOVÁ (203 Czech Republic, belonging to the institution), Yvona BRYCHTOVÁ (203 Czech Republic, belonging to the institution) and Martin TRBUŠEK (203 Czech Republic, guarantor, belonging to the institution)

Edition

Leukemia Research, Oxford, Pergamon Press, 2020, 0145-2126

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.156

RIV identification code

RIV/00216224:14110/20:00115275

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/j.leukres.2019.106288

UT WoS

000509785500002

Keywords in English

Chronic lymphocytic leukemia; TP53/p53; PRIMA-1(MET); Apoptosis

Abstract

V originále

TP53 gene defects represent the most unfavorable prognostic factor in chronic lymphocytic leukemia (CLL). Although recently introduced small-molecule B-cell receptor signalling inhibitors have revolutionized CLL treatment, data for ibrutinib still point to impaired prognosis for TP53-affected patients. Among cancer-associated TP53 mutations, missense substitutions predominate and typically result in a high mutated-p53 protein level. Therefore, rescuing the p53 tumor suppressor function through specific small molecules restoring p53 wild-type (wt) conformation represents an attractive therapeutic strategy for cancer patients with TP53 missense mutations. We tested the effect of mutated-p53 reactivating molecule PRIMA-1(MET) in 62 clinical CLL samples characterized for TP53 mutations and p53 protein level. At the subtle PRIMA-1(MET) concentrations (1-4 mu M), most samples manifested concentration-dependent viability decrease and, conversely, apoptosis induction, with the response being similar in both the TP53-mutated and TP53-wt groups, as well as in the TP53-mutated samples with p53 protein stabilization and without it. PRIMA-1(MET) was able to reduce mutated p53 protein in a proportion of TP53-mutated CLL samples, and this reduction correlated with a significantly stronger viability decrease and apoptosis induction than samples with stable p53 levels. CLL cells are mostly sensitive to PRIMA-1(MET) apart from those with stable mutated p53.

Links

MUNI/A/1105/2018, interní kód MU

Name: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VI (Acronym: VýDiTeHeMA VI)

Investor: Masaryk University, Category A

Citovat

JAŠKOVÁ, Zuzana, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Yvona BRYCHTOVÁ and Martin TRBUŠEK. PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells. Leukemia Research. Oxford: Pergamon Press, 2020, vol. 89, FEB 2020, p. 1-7. ISSN 0145-2126. Available from: https://dx.doi.org/10.1016/j.leukres.2019.106288.

@article{1614689,
   author = {Jašková, Zuzana and Pavlová, Šárka and Malčíková, Jitka and Brychtová, Yvona and Trbušek, Martin},
   article_location = {Oxford},
   article_number = {FEB 2020},
   doi = {http://dx.doi.org/10.1016/j.leukres.2019.106288},
   keywords = {Chronic lymphocytic leukemia; TP53/p53; PRIMA-1(MET); Apoptosis},
   language = {eng},
   issn = {0145-2126},
   journal = {Leukemia Research},
   title = {PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells},
   url = {https://www.sciencedirect.com/science/article/pii/S0145212619307337?via%3Dihub},
   volume = {89},
   year = {2020}
}

TY  - JOUR
ID  - 1614689
AU  - Jašková, Zuzana - Pavlová, Šárka - Malčíková, Jitka - Brychtová, Yvona - Trbušek, Martin
PY  - 2020
TI  - PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells
JF  - Leukemia Research
VL  - 89
IS  - FEB 2020
SP  - 1-7
EP  - 1-7
PB  - Pergamon Press
SN  - 01452126
KW  - Chronic lymphocytic leukemia
KW  - TP53/p53
KW  - PRIMA-1(MET)
KW  - Apoptosis
UR  - https://www.sciencedirect.com/science/article/pii/S0145212619307337?via%3Dihub
L2  - https://www.sciencedirect.com/science/article/pii/S0145212619307337?via%3Dihub
N2  - TP53 gene defects represent the most unfavorable prognostic factor in chronic lymphocytic leukemia (CLL). Although recently introduced small-molecule B-cell receptor signalling inhibitors have revolutionized CLL treatment, data for ibrutinib still point to impaired prognosis for TP53-affected patients. Among cancer-associated TP53 mutations, missense substitutions predominate and typically result in a high mutated-p53 protein level. Therefore, rescuing the p53 tumor suppressor function through specific small molecules restoring p53 wild-type (wt) conformation represents an attractive therapeutic strategy for cancer patients with TP53 missense mutations. We tested the effect of mutated-p53 reactivating molecule PRIMA-1(MET) in 62 clinical CLL samples characterized for TP53 mutations and p53 protein level. At the subtle PRIMA-1(MET) concentrations (1-4 mu M), most samples manifested concentration-dependent viability decrease and, conversely, apoptosis induction, with the response being similar in both the TP53-mutated and TP53-wt groups, as well as in the TP53-mutated samples with p53 protein stabilization and without it. PRIMA-1(MET) was able to reduce mutated p53 protein in a proportion of TP53-mutated CLL samples, and this reduction correlated with a significantly stronger viability decrease and apoptosis induction than samples with stable p53 levels. CLL cells are mostly sensitive to PRIMA-1(MET) apart from those with stable mutated p53.
ER  -

JAŠKOVÁ, Zuzana, Šárka PAVLOVÁ, Jitka MALČÍKOVÁ, Yvona BRYCHTOVÁ and Martin TRBUŠEK. PRIMA-1MET cytotoxic effect correlates with p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells. \textit{Leukemia Research}. Oxford: Pergamon Press, 2020, vol.~89, FEB 2020, p.~1-7. ISSN~0145-2126. Available from: https://dx.doi.org/10.1016/j.leukres.2019.106288.

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