Distinct in vitro sensitivity of p53-mutated and ATM-mutated chronic lymphocytic leukemia cells to ofatumumab and rituximab

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Authors

ŠEBEJOVÁ Ludmila BORSKÝ Marek JAŠKOVÁ Zuzana POTĚŠIL David NAVRKALOVÁ Veronika MALČÍKOVÁ Jitka ŠRÁMEK Martin DOUBEK Michael LOJA Tomáš POSPÍŠILOVÁ Šárka MAYER Jiří TRBUŠEK Martin

Year of publication 2014
Type Article in Periodical
Magazine / Source Experimental Hematology
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://ac.els-cdn.com/S0301472X14002379/1-s2.0-S0301472X14002379-main.pdf?_tid=47198962-9c81-11e4-9496-00000aab0f01&acdnat=1421304158_6115d16ef237cedb9b27da90ac0cf316
Doi http://dx.doi.org/10.1016/j.exphem.2014.06.003
Field Oncology and hematology
Keywords COMPLEMENT-DEPENDENT CYTOTOXICITY; P53 TUMOR-SUPPRESSOR; MONOCLONAL-ANTIBODIES; ATAXIA-TELANGIECTASIA; CD20 EXPRESSION; TP53 MUTATION; 11Q DELETION; FLUDARABINE; CHEMOIMMUNOTHERAPY; DYSFUNCTION
Attached files
Description 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.
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