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Gene expression profiling using extracted RNA from MLL-AF9/Mn1wt and MLL-AF9/Mn1null cells

ABSTRACT: We evaluated the function of Meningioma 1 (MN1), a cofactor of HOXA9 and MEIS1, in murine MLL-r leukemia by CRISPR-Cas9 mediated deletion of MN1. MN1 was required for in vivo leukemogenicity of MLL-r murine and human AML cells. Loss of MN1 inhibited cell cycle and proliferation, promoted apoptosis and induced differentiation of MLL-r cells. Expression analysis and chromatin immunoprecipitation with sequencing demonstrated that MN1 primarily maintains active transcription of HOXA9 and HOXA10, which are critical downstream genes of MLL, and their target genes like BCL2, MCL1 and Survivin.

ORGANISM(S): Mus musculus

PROVIDER: GSE130631 | GEO | 2019/08/15

REPOSITORIES: GEO

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Project description:Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic molecular marker in adult AML with normal cytogenetics, however its role in pediatric leukemia is unknown. We found elevated MN1 expression in 53 of 88 pediatric leukemia cases: significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia but no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL). Interestingly 17 of 19 cases harboring MLL-X fusions showed also elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM13). In a mouse MLL/ENL-induced leukemia MN1 overexpression resulted from retroviral provirus insertion. Strikingly co-expression of MN1 with MLL/ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. MN1 overexpression in MLL/ENL-carrying cells resulted in expansion of the L-GMP population and facilitated disease induction in secondary recipients. Gene expression profiling allowed to define a number of potential MN1 hematopoietic targets. Up-regulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse leukemias, as well as in some cases of pediatric leukemias overexpressing MN1. Taken together, our work suggests that MN1 overexpression is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-X fusion genes most probably through modification of a distinct gene expression program that leads to expansion of a leukemia initiating cell population. In three independent experiments bone marrow cells were transduced with MSCV-MN1-IRES/YFP or empty vector. 72h after transduction EYFP-positive cells were FACS-sorted and RNA isolated by ion-exchange chromatography with RNAmini (Qiagen) according to the manufacturerâs protocol

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Gene expression profiling using extracted RNA from MLL-AF9/Mn1wt and MLL-AF9/Mn1null cells

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