Abstract
AbstractDespite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs.
Highlights
Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal
Because the inhibition of polymerase I (Pol I) transcription altered the expression of genes involved in granulocyte development and myeloid differentiation (Figure 6C; supplemental Figure 8A), we examined the effect of CX-5461 on AML tumor cell differentiation
We show that pharmacologic inhibition of Pol I transcription robustly reduced clonogenic capacity of AML in vitro and leukemia-initiating cell (LIC) in vivo
Summary
Acute myeloid leukemia (AML) is a clinically heterogeneous disease characterized by a multitude of gene mutations and chromosomal abnormalities, resulting in marked differences in responses and survival following chemotherapy. Analysis of the hematopoietic compartment reveals that CX-5461 reduces the LIC population in p53 wild-type (WT) and null AML, decreasing the disease-initiating potential in vivo and their clonogenic capacity Together, these studies suggest that Pol I transcription inhibition may represent a promising new approach to treat human. Overall survival of CX-5461 (40 mg/kg every 3 days, 6 doses total, start of therapy day 20 pt, and last dose day 35 pt) and vehicle-treated AML1/ETO9a Nras p53WT leukemia-bearing mice (****P , .0001; n 5 10 per group).
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