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

Abstract : Multiple myeloma is a plasma cell malig-nancy that is heterogeneous with respectto its causative molecular abnormalitiesand the treatment response of patients.The Bcl-2 protein family is critical formyeloma cell survival. ABT-737 is a cell-permeant compound that binds to Bcl-2and Bcl-xLbut not to Mcl-1. Using amyeloma cell line collection (n25) rep-resentative of different molecular translo-cations, we showed that ABT-737 effec-tively kills a subset of cell lines (n6),with a median lethal dose ranging from70.4nM to 1507.5nM. Of interest, allsensitive cell lines harbored a t(11;14).We demonstrated that ABT-737–sensitiveand ABT-737–resistant cell lines could bedifferentiated by theBCL2/MCL1expres-sion ratio. A screen of a public expres-sion database of myeloma patients indi-cates that theBCL2/MCL1ratio of t(11;14)and hyperdiploid patients was signifi-cantly higher than in all other groups(P<.001). ABT-737 first induced the dis-ruption of Bcl-2/Bax, Bcl-2/Bik, or Bcl-2/Puma complexes, followed by the disrup-tion of Bcl-2 heterodimers with Bak andBim. Altogether, the identification of asubset of cell lines and primary cellseffectively killed by ABT-737 alone sup-ported the evaluation of ABT-263, an orallyactive counterpart to ABT-737, for thetreatment of t(11;14) and hyperdiploidgroups of myeloma harboring a Bcl-2high/Mcl-1lowprofile.
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Linda Bodet, Patricia Gomez-Bougie, Cyrille Touzeau, Christelle Dousset, Géraldine Descamps, et al.. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood, American Society of Hematology, 2011, 118 (14), pp.3901 - 3910. ⟨10.1182/blood-2010-11-317438⟩. ⟨inserm-03290338⟩



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