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Editorials
   highest MN1 transcript levels were associated with a higher incidence and shorter time to relapse.14
How can we then therapeutically target MN1 expres- sion? Although useful to provide proof of concept in experimental studies, clinical siRNA-based knockdown approaches, such as those used by Sharma et al., have so far been hampered by limited delivery into the target cells. However, small molecules have been generated that can interfere with certain transcription factor/co-factor pro- tein-protein interactions or with transcription factor-DNA binding. In addition, transcription activity was successful- ly targeted by altering levels of ubiquitylation and subse- quent proteasome degradation or by interference with regulators of transcription factor expression.18 To target MN1 as a transcription factor, we would need to know its potential interaction partners on chromatin and/or the critical domains of MN1 that are necessary to maintain the transformed state of AML cells. Targeted genome edit- ing screens could offer a platform to dissect structural needs of MN1 activity in AML cells.19 Previous work that explored the transforming potential of a large number of MN1 deletion mutants suggested that 221 N-terminal amino acids are critical for induction of AML in vivo asso- ciated with expression of HOXA9, HOXA10 and MEIS2.20 Similarly, others reported that MN1 lacking amino acids 12-228 was unable to induce leukemia in the BM reconsti- tution assay, suggesting that overexpression of N-terminal MN1 peptides and small molecules “mimicks” might be able to compete with potentially, yet to be defined, critical protein and/or chromatin interactions.21 Interestingly, the N-terminal region of MN1 was also shown to interact with the EP300 transcriptional co-activator, raising the question as to whether AML cells expressing high MN1 levels would be particularly sensitive to recently devel- oped small molecule EP300 inhibitors.22,23
Collectively, by demonstrating a critical role for MN1 in AML maintenance, the work by Sharma et al. suggests that targeting the aberrantly high levels of MN1 expres- sion would have strong anti-leukemic activity. However, the AML patients that would profit from such interven- tion, and the most efficient clinically applicable strategy, remain to be elucidated.
Acknowledgments
This work was supported by grants from the Swiss Cancer League (KFS-3487-08-2014) and the Swiss National Science Foundation (SNF, 31003_A_173224/1).
References
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