MYC and p53 are critical nodes in chronic myeloid leukemia (CML) leukemic stem cells.

  • Major finding: MYC and p53 are critical nodes in chronic myeloid leukemia (CML) leukemic stem cells.

  • Mechanism: MYC inhibition promotes CML CD34+ cell differentiation, and p53 stabilization induces apoptosis.

  • Impact: Dual targeting of p53 and MYC may eliminate CML stem cells to allow for curative therapy.

Chronic myeloid leukemia (CML) is driven by the fusion tyrosine kinase BCR–ABL, which transforms hematopoietic stem cells (HSC). Tyrosine kinase inhibitors (TKI) have been effective in treating CML, but do not kill the leukemic stem cells (LSC), which persist in a BCR–ABL-independent manner. Abraham, Hopcroft, and colleagues therefore sought to identify critical kinase-independent protein networks in CML that could potentially be exploited for curative therapies. Isobaric-tag mass spectrometry identified deregulated proteins in treatment-naïve CML compared with normal CD34+ HSCs, and revealed p53 and MYC as central nodes in a 30-protein CML network, with p53 targets primarily downregulated in CML, and MYC targets both upregulated and downregulated. To test the hypothesis that p53 activation and MYC inhibition would kill LSCs, MYC and p53 were targeted using RITA, which binds to p53 and blocks its degradation by HDM2, and CPI-203, a bromodomain and extra terminal protein (BET) inhibitor that downregulates MYC. Treatment of CML CD34+LSCs cells with either RITA or CPI-203 reduced cell viability, and the combination was synergistic. CPI-203 resulted in a rapid loss of CD34 expression, suggesting that MYC inhibition promoted differentiation of CD34+ CML cells, whereas RITA enhanced apoptosis, suggesting that p53 stabilization enhanced cell death. Normal CD34+ cells were not susceptible to treatment with RITA and CPI-203, whereas the long-term engrafting potential of treated leukemic cells was significantly decreased, indicating that RITA and CPI-203 selectively target CML LSCs. In preclinical mouse models of CML, combination therapy with BET inhibitors and HDM2 inhibitors currently in clinical trials was well tolerated, and synergistically reduced leukemic cells in the bone marrow. Together, these findings reveal a critical importance of the p53 and MYC signaling network in CML LSCs, which may be exploited to eradicate CML LSCs and develop curative CML therapies.

Abraham SA, Hopcroft LE, Carrick E, Drotar ME, Dunn K, Williamson AJ, et al. Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature 2016;534:341–6.

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