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Series GSE146362 Query DataSets for GSE146362
Status Public on Jun 01, 2020
Title Comprehensive comparison and biologic activity of novel therapeutic agents in NPM1 mutated Acute Myeloid Leukemia (AML)
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Acute 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 biological activity in NPM1c+ cell line IMS-M2, these cells were resistant to BETi exposure, except for nuclear re localization of NPM1 which is a general phenomenon upon treatment with all three drug types. Gene profiling revealed that BRDi downregulate a BRD specific core gene signature in OCI-AML3 and IMS-M2 cells but IMS-M2 cells yield a transcriptional resistance signature including upregulation of the Wnt/beta-catenin pathway. HOX gene clusters in OCI-AML3 cells and IMS-M2 cells are heterogeneously regulated by BETi and are down regulated by ATO+ATRA in line with results reported for Selinexor treatment. Taken together, our preclinical results encourage clinical testing of ATO+ATRA, Selinexor and BRDi in NPM1c+ AML patients.
 
Overall design Comparison of drugs ATO+ATRA, ATO, ATRA, JQ1, OTX015 and DMSO in IMS-M2 and OCI AML3 leukemic cell lines
 
Contributor(s) Djamai H, Berrou J, Dupont M, Coudé M, Delord M, Clappier E, Kaci A, Raffoux E, Itzykson R, Berthier C, de Thé H, Baruchel A, Gardin C, Dombret H, Braun T
Citation(s) 34829934
Submission date Mar 04, 2020
Last update date Dec 09, 2021
Contact name Marc Delord
E-mail(s) mdelord@gmail.com
Organization name Centre hospitalier de Versailles
Department Recherche clinique
Street address Hopital Saint-Louis, 1 avenue Claude Vellefaux
City Paris
ZIP/Postal code 75010
Country France
 
Platforms (1)
GPL17586 [HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version]
Samples (36)
GSM4378908 leukemic cell line IMS_M2 treated with ATO_ATRA replicate 1
GSM4378909 leukemic cell line IMS_M2 treated with ATO_ATRA replicate 2
GSM4378910 leukemic cell line IMS_M2 treated with ATO_ATRA replicate 3
Relations
BioProject PRJNA610255

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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE146362_RAW.tar 914.2 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table
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