Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Abstract

Key Points• Inhibition of RNA Pol I by CX-5461 treats aggressive AML and outperforms standard chemotherapy regimens.• CX-5461 induces p53-dependent apoptosis, p53-independent cell-cycle defects and differentiation, and reduces LICs.Despite 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. (Blood. 2017;129(21):2882-2895

Histone Modification Patterns Using RPPA‐Based Profiling Predict Outcome in Acute Myeloid Leukemia Patients

“…High levels of NCL , recently identified as an adverse prognostic factor in AML, were also observed in the HMP on clusters . NCL affects epigenetic regulation by acting as histone chaperone and as transcription regulator of RNA polymerase 1 ( Pol 1 ), whose overexpression is associated with increased gene expression resulting in altered apoptosis, differentiation, and initiation of leukemia cells . The high levels of NCL in the on cluster in our study may therefore be associated with higher Pol 1 transcription, resulting in protection against apoptosis, a block in differentiation and expansion of the stem cell pool, all of which would be associated with increased chemoresistance.…”

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

“…Morphological changes in the nucleoli, the sites of Pol I transcription and ribosome subunit assembly, have been associated with poor cancer prognosis for over 100 years (18). We and others have demonstrated targeting Pol I transcription as a novel approach for cancer treatment (19)(20)(21)(22). Inhibition of Pol I transcription using the specific small-molecule inhibitor CX-5461 can selectivity kill cancer cells in vivo (19,20,23).…”

“…We and others have demonstrated targeting Pol I transcription as a novel approach for cancer treatment (19)(20)(21)(22). Inhibition of Pol I transcription using the specific small-molecule inhibitor CX-5461 can selectivity kill cancer cells in vivo (19,20,23). CX-5461 is currently in phase I clinical trials in patients with haematological malignancies (ACTRN12613001061729) (24) and solid tumors (Canadian Cancer Trials Group, NCT02719977) (25).…”

Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

“…We developed the "first in class" selective inhibitor of ribosome biogenesis, CX-5461, which targets RNA Polymerase I (Pol I) transcription, suppressing ribosomal RNA (rRNA) synthesis (7). Moreover, we demonstrated its in vivo efficacy in mouse models of both blood and prostate cancer (7)(8)(9)(10)(11). These studies served as the basis for testing CX-5461 in clinical trials in patients with refractory blood cancers and solid tumors (12,13).…”