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Editorials
loop between FLT3 and HOXA9 / MEIS1 expression. Enforced FLT3 expression leads to upregulation of HOXA9 and MEIS1, and enforced expression of HOXA9 and MEIS1 in turn results in upregulation of FLT3. In addition, looking at all of the genes that had reduced expression after HHT administration, the authors found a significant enrichment of MYC target genes. They were then able to confirm that MYC expression itself was reduced after HHT treatment. Myc is one of the master regulators of cellular growth, increasing ribosome biogen- esis and protein synthesis.13
SP1 is a transcription factor which has many cognate binding sites in the promoter region of many genes. So what is the evidence that the HHT-mediated inhibition of SP1 binding to the TET1 promoter is critical for the phe- notype observed in AML cells after HHT treatment and not the repression of a number of other genes? Very ele- gantly, the authors showed that repression of TET1 phe- nocopies the effect of HHT treatment.
In summary, by binding to the transcription factor SP1, HHT affects one of the core pathways that are responsi- ble for growth (MYC and targets) and impaired differen- tiation (HOXA9 and MEIS1) of AML cells. The central players in this pathway are the dioxygenase TET1 and the receptor tyrosine kinase FLT3. FLT3-activating muta- tions are found in about 40% of AML cases and it is over- expressed in an even larger proportion of AML. Thus, HHT promises to be effective in the majority of AML cases. HHT might thus be efficacious in a larger number of AML patients than several of the more recently intro- duced targeted AML drugs like FLT3 inhibitors (e.g. midostaurin, gilteritinib), IDH1/2 inhibitors (enasidenib, evosidenib), or hedgehog pathway inhibitors (glasdeg- ib).14 At the same time, one would hope that it is more specific for AML than conventional chemotherapeutic agents such as nucleoside analogs or anthracyclines, which affect very basic cellular functions like DNA metabolism and are thus highly toxic to normal cells.
Figure 1. Diagram of the pathways affected by homoharringtonine (HHT). (A) Status of the pathways in the leukemic cells in the absence of HHT. (B) When HHT is present, it binds to SP1 which leads to a reduction of the activity of downstream pathways.
haematologica | 2020; 105(1)