ŠEBEJOVÁ, Ludmila, Marek BORSKÝ, Zuzana JAŠKOVÁ, David POTĚŠIL, Veronika NAVRKALOVÁ, Jitka MALČÍKOVÁ, Martin ŠRÁMEK, Michael DOUBEK, Tomáš LOJA, Šárka POSPÍŠILOVÁ, Jiří MAYER and Martin TRBUŠEK. Distinct in vitro sensitivity of p53-mutated and ATM-mutated chronic lymphocytic leukemia cells to ofatumumab and rituximab. Experimental Hematology. New York: Elsevier Science Inc, 2014, vol. 42, No 10, p. 867-874. ISSN 0301-472X. doi:10.1016/j.exphem.2014.06.003.
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Basic information
Original name Distinct in vitro sensitivity of p53-mutated and ATM-mutated chronic lymphocytic leukemia cells to ofatumumab and rituximab
Authors ŠEBEJOVÁ, Ludmila (203 Czech Republic, belonging to the institution), Marek BORSKÝ (203 Czech Republic, belonging to the institution), Zuzana JAŠKOVÁ (703 Slovakia, belonging to the institution), David POTĚŠIL (203 Czech Republic, belonging to the institution), Veronika NAVRKALOVÁ (203 Czech Republic, belonging to the institution), Jitka MALČÍKOVÁ (203 Czech Republic, belonging to the institution), Martin ŠRÁMEK (203 Czech Republic, belonging to the institution), Michael DOUBEK (203 Czech Republic, belonging to the institution), Tomáš LOJA (703 Slovakia, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution), Jiří MAYER (203 Czech Republic, belonging to the institution) and Martin TRBUŠEK (203 Czech Republic, guarantor, belonging to the institution).
Edition Experimental Hematology, New York, Elsevier Science Inc, 2014, 0301-472X.
Other information
Original language English
Type of outcome Article in a journal
Field of Study 30200 3.2 Clinical medicine
Country of publisher United States of America
Confidentiality degree is not subject to a state or trade secret
WWW URL
Impact factor Impact factor: 2.475
RIV identification code RIV/00216224:14740/14:00078349
Organization unit Central European Institute of Technology
Doi http://dx.doi.org/10.1016/j.exphem.2014.06.003
UT WoS 000343791500005
Keywords in English COMPLEMENT-DEPENDENT CYTOTOXICITY; P53 TUMOR-SUPPRESSOR; MONOCLONAL-ANTIBODIES; ATAXIA-TELANGIECTASIA; CD20 EXPRESSION; TP53 MUTATION; 11Q DELETION; FLUDARABINE; CHEMOIMMUNOTHERAPY; DYSFUNCTION
Tags EL OK, kontrola MP, ok, podil, podíl ceitec, rivok
Tags International impact, Reviewed
Changed by Changed by: Martina Prášilová, učo 342282. Changed: 28. 1. 2015 13:52.
Abstract
Abnormalities in ATM and TP53 genes represent important predictive factors in chronic lymphocytic leukemia (CLL); however, the efficacy of CD20 targeting immunotherapy is only poorly defined in the affected patients. Therefore, we tested the in vitro response to ofatumumab (OFA) and rituximab (RTX) in 75 CLL samples with clearly defined p53 or ATM inactivation. Using standard conditions allowing complement-dependent cytotoxicity, i.e., 10 mu g/mL of antibodies and 20% active human serum, we observed clear differences among the tested genetic categories: ATM-mutated samples (n = 17) represented the most sensitive, wild-type samples (n = 31) intermediate, and TP53-mutated samples (n = 27) the most resistant group (ATM-mut vs. TP53-mut: P = 0.0005 for OFA and P = 0.01 for RTX). The response correlated with distinct levels of CD20 and critical complement inhibitors CD55 and CD59; CD20 level median was the highest in ATM-mutated and the lowest in TP53-mutated samples (difference between the groups P < 0.01), while the total level of complement inhibitors (CD55 plus CD59) was distributed in the opposite manner (P < 0.01). Negligible response to both OFA and RTX was noted in all cultures (n = 10) tested in the absence of active serum, which strongly indicated that complement-dependent cytotoxicity was a principal cell death mechanism. Our study shows that (1) common genetic defects in CLL cells significantly impact a primary response to anti-CD20 monoclonal antibodies and (2) ATM-mutated patients with currently poor prognosis may potentially benefit from immunotherapy targeting CD20. (C) 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.
Links
MUNI/A/0830/2013, interní kód MUName: Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit (Acronym: VýDiTeHeMa)
Investor: Masaryk University, Category A
NT13519, research and development projectName: Časná identifikace CLL pacientů s dosud nevyselektovanými mutacemi v proteinu p53
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