Poster Presentation 40th Annual Lorne Genome Conference 2019

Investigating the potential use of RNA polymerase 1 transcription inhibitors in the treatment of MDS (#120)

Daniela P Borges 1 2 , Sarah S Maranhao 1 3 , Katherine Hannan 1 , Amee George 1 , Rita Ferreira 1 , Ronald F Pinheiro 2 , Ross Hannan 1
  1. Australian National University, Canberra, ACT, Australia
  2. Cancer Cytogenomic Laboratory, Federal University of Ceará, Fortaleza, Ceará, Brazil
  3. Laboratory of Experimental Oncology, Federal University of Ceará, Fortaleza, Ceará, Brazil

The Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal diseases characterized by bone marrow insufficiency and an increase of apoptosis, leading to ineffective hematopoiesis and increased risk of progression to acute myeloid leukemia (AML). The treatment for MDS is very limited, especially for high-risk patients, that are usually treated with hypomethylating agents (HMAs) to try to prevent the AML evolution. Unfortunately, 40 to 60% of the patients do not respond to treatment.

CX-5461 is a novel selective inhibitor of RNA polymerase I (Pol I) transcription that has been recently shown to treat aggressive AML, independent of TP53 status, in xenograft models. The behavior of CX-5461 in AML suggests that Pol I inhibitors may have a positive effect on the treatment of MDS, especially for high-risk MDS and AML evolution.

In this work we are testing the effect of RNA Pol I inhibitors (CX-5461, BMH-21 and PMR-116) in MDS, comparing the efficacy of the inhibitors in MDS cell lines versus AML (MDS and non-MDS derived) cell lines, using cell proliferation and differentiation assays and expression analysis of genes related to MDS pathogenesis and Pol I transcription. The results obtained with the cell lines will be compared to patient’s primary cells and to standard therapy for MDS. We aim to discover novel therapeutics strategies that can improve MDS patients outcome.

  1. Adès L, Itzykson R, Fenaux P. Myelodysplastic syndromes. The Lancet. 2014; 383(9936): 2239 - 2252.
  2. Pfeilstöcker M, Tuechler H, Sanz G, Schanz J, et al. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016; 128:902-910.
  3. Cluzeau T, Robert G, Karsenti JM, et al. BCL2L10 is associated with resistance to azacitidine (AZA) in MDS and AML, and is a possible target in resistant patients. Leuk Res 2013; 37:S78.
  4. Santini V, Prebet T, Fenaux P, et al. Minimizing risk of hypomethylating agent failure in patients with higher-risk MDS and practical management recommendations. Leukemia Research. 2014; 38:1381-1391.
  5. Hein N, et al. Inhibition of Pol I transpition treats murine and human AML by targeting the leukemia-initiating cell population. Blood. 2017; 129(21).