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Dual Targeting of p53 and c-MYC Eradicates Leukemic Stem Cells

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Review of “Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells” from Nature by Stuart P. Atkinson

The formation of the BCR-ABL1 chimeric oncogene generates a constitutively active protein tyrosine kinase (PTK) [1] whose activity in hematopoietic stem cells (HSCs) mediates the development of chronic myeloid leukemia (CML). Various treatment strategies can improve survival in CML patients, although the aberrant leukemic stem cells which cause the disease remain unharmed and can cause disease re-emergence [2].

The laboratory of Tessa L. Holyoake (University of Glasgow, UK) knew this fact all too well and set out to identify putative druggable targets in leukemic stem cells using unbiased transcriptomic and proteomic analyses. In their new Nature study, they now show the fruits of this study: dual targeting of p53 and c-MYC eradicates CML leukemic stem cells and may allow for the complete remission of the disease [3].

The study initially employed two systems to compare CML and normal CD34+ hematopoietic stem/progenitor cells: isobaric-tag mass spectrometry to study protein deregulation and primary CML transcriptomic data to study RNA deregulation. Interestingly, this found that p53 and c-MYC “controlled” a significant proportion of the deregulated RNA/protein expression.

This suggested that targeting these two key factors may specifically and effectively target CML CD34+ cells. To do this, the authors employed two drugs: RITA, to enhance p53 stability, and CPI-203, a bromodomain and extra terminal protein (BET) inhibitor which downregulates c-MYC expression. RITA/CPI-203 dual treatment reduced cell viability, increased apoptosis, and also enhanced differentiation of CML CD34+ cells whilst exhibiting no great effect on normal CD34+ cells. Importantly, the authors then extended these findings to show that RITA/CPI-203 also specifically targeted and eliminated the leukemic stem cells which drive CML which from part of the CD34+ cell population.

The study next aimed to show the clinical relevance of their findings using a preclinical mouse model of CML and the application of drugs already advanced in clinical trials in human (RG7112/RG7388 to enhance p53 stability and CPI-0610, a known BET inhibitor). Encouragingly, mice tolerated modest doses of the drug combination and white blood cell and neutrophil counts returned back to non-leukemic control levels. Furthermore, combination treatment also reduced the numbers of leukemic stem cells whilst leaving the normal stem cells unaffected. Finally, and most interestingly of all, the authors also observed the anti-leukemic stem cells effects of the combination treatment in mice carrying with human CD34+ cells.

For years, studies and trials have targeted the BCR-ABL fusion gene in an attempt to defeat CML, but now, using an unbiased systems approach, these intrepid researchers have uncovered a new and much more effective treatment strategy. This dual strategy eradicates leukemic stem cells, spares normal HSCs, is well tolerated, and will be less susceptible to resistance in the long term. We only hope that these exciting new results now join the few other CML-based studies whose findings have successfully reached pre-clinical/clinical trials [4, 5].

References

  1. O'Hare T, Zabriskie MS, Eiring AM, et al. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer 2012;12:513-526.
  2. Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002;99:319-325.
  3. Abraham SA, Hopcroft LE, Carrick E, et al. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature 2016;534:341-346.
  4. Zhang B, Strauss AC, Chu S, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 2010;17:427-442.
  5. Prost S, Relouzat F, Spentchian M, et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPARgamma agonists. Nature 2015;525:380-383.