ABT-737 is highly effective against molecular subgroups of multiple myeloma

被引：102

作者：

Bodet, Linda ^{[1
,2
]}

Gomez-Bougie, Patricia ^{[1
,2
,3
]}

Touzeau, Cyrille ^{[1
,3
]}

Dousset, Christelle ^{[1
,2
,3
]}

Descamps, Geraldine ^{[1
,2
]}

Maiga, Sophie ^{[1
,2
]}

Avet-Loiseau, Herve ^{[3
]}

Bataille, Regis ^{[1
,2
]}

Moreau, Philippe ^{[3
]}

Le Gouill, Steven ^{[1
,3
]}

Pellat-Deceunynck, Catherine ^{[1
,2
]}

Amiot, Martine ^{[1
,2
]}

机构：

[1] Univ Nantes, Inst Rech Therapeut, INSERM, UMR S892, Nantes, France

[2] Equipe 10 Labellisee Ligue Natl Canc 2008, Nantes, France

[3] CHU Nantes, Dept Hematol Clin & Biol, F-44035 Nantes 01, France

来源：

BLOOD | 2011年 / 118卷 / 14期

关键词：

BCL-2; FAMILY-MEMBERS; BH3 MIMETIC ABT-737; CELL-LINES; APOPTOSIS; SENSITIVITY; INHIBITOR; PROTEINS; LEUKEMIA; CLASSIFICATION; SURVIVAL;

D O I：

10.1182/blood-2010-11-317438

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Multiple myeloma is a plasma cell malignancy that is heterogeneous with respect to its causative molecular abnormalities and the treatment response of patients. The Bcl-2 protein family is critical for myeloma cell survival. ABT-737 is a cell-permeant compound that binds to Bcl-2 and Bcl-x(L) but not to Mcl-1. Using a myeloma cell line collection (n = 25) representative of different molecular translocations, we showed that ABT-737 effectively kills a subset of cell lines (n = 6), with a median lethal dose ranging from 7 +/- 0.4nM to 150 +/- 7.5nM. Of interest, all sensitive cell lines harbored a t(11;14). We demonstrated that ABT-737-sensitive and ABT-737-resistant cell lines could be differentiated by the BCL2/MCL1 expression ratio. A screen of a public expression database of myeloma patients indicates that the BCL2/MCL1 ratio of t(11; 14) and hyperdiploid patients was significantly higher than in all other groups (P < .001). ABT-737 first induced the disruption of Bcl-2/Bax, Bcl-2/Bik, or Bcl-2/Puma complexes, followed by the disruption of Bcl-2 heterodimers with Bak and Bim. Altogether, the identification of a subset of cell lines and primary cells effectively killed by ABT-737 alone supported the evaluation of ABT-263, an orally active counterpart to ABT-737, for the treatment of t(11; 14) and hyperdiploid groups of myeloma harboring a Bcl-2(high)/Mcl-1(low) profile. (Blood. 2011;118(14):3901-3910)

引用

页码：3901 / 3910

页数：10

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