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Farsky seeds12/29/2023 ![]() ![]() Thus, new approaches for treating MLL-r leukemia use small molecules that specifically block the interaction of MLL fusion proteins with transcriptional complexes containing Menin ( Grembecka et al., 2012), DOT1L ( Daigle et al., 2011), and BET family proteins ( Dawson et al., 2011) or inhibit key MLL target genes, such as CDK6 ( Placke et al., 2014), which are known to be important for the transformation and maintenance of this leukemia subgroup. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.Įxpression of MLL fusion proteins, such as MLL-AF9, is sufficient to transform normal bone marrow hematopoietic stem/progenitor cells ( Corral et al., 1996 Krivtsov et al., 2006 Somervaille and Cleary, 2006 Chen et al., 2008b). Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27 Kip1 and inhibited human AML growth. Conversely, elevation of p27 Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. We found Cdkn1b (p27 Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo.
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