GSE146362 Comprehensive comparison and biologic activity of novel therapeutic agents in NPM1 mutated Acute Myeloid Leukemia (AML)

Contributors : Hanene Djamai ; Jeannig Berrou ; M élanie Dupont ; Marie-Magdelaine Coudé ; Marc Delord ; Emmanuelle Clappier ; Anna Kaci ; Emmanuel Raffoux ; Raphaël Itzykson ; Caroline Berthier ; Hugues de Thé ; André Baruchel ; Claude Gardin ; Hervé Dombret ; Thorsten BraunSeries Type : Expression profiling by arrayOrganism : Homo sapiensAcute Myeloid Leukemia (AML) is frequently associated with mutations of NPM1 (NPM1c+) and even if considered to be of better prognosis for younger patients, relapse is frequent and outcome remains poor for elder patients with a need for novel treatment strategies. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) induce proteasomal degradation of NPM1c protein, NPM1 nuclear re localization, differentiation and apoptosis in NPM1c+ cells and blast clearance in relapsed/refractory AML patients. In line, the XPO1 inhibitor Selinexor showed similar results in vitro associated with down regulation of a specific HOX gene signature. BET inhibitors (BETi) OTX015 (MK-8628) and JQ1 yield antileukemic activity and here we demonstrate their effects in NPM1c+ leukemia cells compared to ATO+ATRA and Selinexor. Compared to ATO+ATRA and Selinexor, BRDi induced TP53 independent apoptosis, differentiation, proteasomal NPM1c degradation and nuclear relocalization in NPM1c+ OCI-AML3 cell line and to different extend in patient derived blast cells. As ATO+ATRA and Selinexor had significant b...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research