Dataset Information

Effect of Miz1 POZ domain deletion on expression profiles of B and T leukemia cells

ABSTRACT: Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer mainly affecting children. Relapse rates are high and toxic chemotherapies that block DNA replication and induce DNA damage cause health problems later in life, underlining the need for improved therapies. c-Myc is a transcription factor that is hyperactive in a large proportion of cancers including leukemia but is difficult to target in therapy. We show that ablation of the function of the BTB/POZ domain factor Miz-1, an important co-factor of c-Myc, significantly delays T- and B-ALL/lymphoma in mice and interferes with c-Myc oncogenic transcriptional activity. Leukemic cells that still emerge in this system activate DNA replication pathways, which are those targeted by current chemotherapeutic drugs such as cytarabine. We found that the combination of acute ablation of the Miz-1 POZ domain enhances the effect of cytarabine treatment. This combination was effective in both Eµ-Myc and Notch ICN driven leukemia models and prolonged survival of tumor bearing animals by accelerating apoptosis of leukemic cells. These observations suggest that targeting Miz-1 could render current ALL chemotherapies more effective with a better outcome for patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE120001 | GEO | 2019/09/30

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and âreprogramsâ the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development. In this study, we show that Myc and N-myc differ in their affinity for Miz1, and Myc/Miz1 interaction is required for Group3 medulloblastoma (MB). The gene expression profiles of these tumors were compared to our previously published Group3 MB model as well as SHH model of MB (Kawachi et al., 2012, Cancer Cell). Cerebellar granule neuron progenitors (GNPs) [dka220-222] from postnatal (P) 6 Math1-GFP;Trp53-/-;Cdkn2c-/-. For SHH medulloblastomas, [dka204-206] and [blm015-017 or dka050-dka051], spontaneous medulloblastomas from Cdkn2c-/-;Trp53Fl/Fl;Nestin-Cre (Kawachi et al., 2012, Cancer Cell) and Ptch1+/-;Cdkn2c-/- (Uziel et al., 2005, Genes Dev) were used, respectively. Myc- [dka201-203] and MycV394D (termed MycVD thereafter)- [bvo017-bvo023] tumors were from Trp53-/-;Cdkn2c-/- cerebella of P6-P7 pups. Myc/ÎPOZ tumors [bvo002-bvo006] were obtained from Trp5Fl/Fl;Miz1ÎPOZ/POZ;Nestin-Cre cerebella of P6-P7 pups.

Dataset Information

Effect of Miz1 POZ domain deletion on expression profiles of B and T leukemia cells

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets