Expression profiling of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D post treatment with Dot1l inhibitor (Microarray)
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ABSTRACT: DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided gene expression profiling data for (1) RH-RAS leukemia stem cells (RH-RAS LSCs), (2) LSCs transformed by MLL-AF9, (3) LSCs transformed by NUP98-JARID1A, and (4) Dot1l inhibitor-treated RH-RAS LSCs.
ORGANISM(S): Mus musculus
PROVIDER: GSE71439 | GEO | 2016/06/23
SECONDARY ACCESSION(S): PRJNA291209
REPOSITORIES: GEO
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