General AML

Pol I transcription inhibition can treat aggressive AML

Acute Myeloid Leukemia (AML) driven by translocations involving Mixed-Lineage Leukemia (MLL) is an aggressive subtype characterized by poor prognosis. There is a need for new therapeutic agents to treat these aggressive AML subtypes, hence the rationale for this study.

Nadine Hein, from The John Curtin School of Medicine, and colleagues investigated the therapeutic efficacy and mechanism of CX-5461, a novel inhibitor of RNA Polymerase I (Pol I), in AML driven by MLL fusion proteins. The results of the study were published ahead of print in Blood on 10 March 2017.

The key results of the study were:
  • In mice transplanted with p53WT expressing MLL fusion proteins (M/E and MA9), continuous CX-5461 administration significantly delayed disease progression
  • Compared to standard chemotherapy (cytarabine/doxorubicin), CX-5461 significantly prolonged survival in mice transplanted with p53WT expressing MLL fusion proteins
  • Treatment of mice engrafted with p53null M/E leukemia with CX-5461 delayed disease progression and prolonged survival
  • CX-5461 treatment of human AML cells (with different p53 status) induced phosphorylation of Checkpoint Kinase 1 (CHK1) and 2 (CHK2), and led to aberrant cell cycle progression accumulating in the G2/M phase
  • CX-5461 treatment induced myeloid differentiation of leukemic blasts and an increased expression of Mac-1 (myeloid differentiation marker)
  • Single dose of CX-5461 reduced the Leukemic Granulocyte-Macrophage Progenitor (LGMP) population in mice transplanted with MLL p53WT and MLL p53 null
  • The frequency of Leukemia Initiating Cells (LICs) was significantly reduced in CX-5461 treated M/E mice compared to naïve treated M/E mice

In summation, CX-5461 mediated inhibition of Pol 1 can treat aggressive AML effectively compared to standard chemotherapy. Moreover, CX-5461 induced p53-independent cell cycle and decreased the frequency of LICs. Additionally, the authors suggested that inhibition of Pol I “may represent a promising new approach to treat human AML by targeting the LIC independent of functional p53”.

The authors concluded by stating that their results demonstrate that CX-5461 can effectively treat aggressive hematological malignancies. Furthermore, inhibition of Pol I transcription may be broadly beneficial in a variety of hematological malignancies with TP53 mutations. Based on this preclinical data, a phase I open-label study (12613001061729, Australian New Zealand Clinical Trials Registry) is currently underway. In this study, the maximum tolerated dose of CX-5461 is being evaluated in patients with advanced hematological malignancies including relapsed or refractory AML.

Abstract

Despite the development of novel drugs, 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 MLL-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461, the induction of p53-dependant apoptotic cell death, 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 CHK1/CHK2, 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, 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 leukemia initiating cells.

References
  1. Hein N. et al. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood. 2017 Mar 10. DOI: 1182/blood-2016-05-718171. [Epub ahead of print].