Abstract
PPARγ agonists synergize with the BCR–ABL inhibitor imatinib to deplete the CML stem cell pool.
Major finding: PPARγ agonists synergize with the BCR–ABL inhibitor imatinib to deplete the CML stem cell pool.
Mechanism: PPARγ agonists inhibit the PPARγ–STAT5–HIF2α–CITED2 pathway, driving CML stem cell apoptosis.
Impact: Combination PPARγ agonist and TKI therapy shows early clinical efficacy in phase II trials.
In chronic myeloid leukemia (CML), BCR–ABL tyrosine kinase inhibitors (TKI) such as imatinib improve patient survival but rarely achieve complete molecular response (CMR) because of their inability to eradicate quiescent CML stem cells. It has previously been shown that the antidiabetic drugs pioglitazone and rosiglitazone, which function as agonists of peroxisome proliferator-activated receptor γ (PPARγ), impair hematopoiesis in CD34+ CML cell lines. Prost and colleagues found that pioglitazone and rosiglitazone synergized with imatinib to decrease the number of colony-forming cells in patients with chronic-phase CML. Imatinib reduced the number of progenitor cells, whereas pioglitazone reduced the number of immature leukemia stem cells, and in combination these agents depleted both proliferating and nonproliferating CD34+ CML cells. Mechanistically, pioglitazone decreased expression of STAT5, which is transcriptionally repressed by PPARγ, and the downstream targets hypoxia-inducible factor 2α (HIF2A) and CITED2, key genes that regulate the stemness of hematopoietic stem cells. Whereas imatinib acted rapidly to prevent STAT5 phosphorylation, pioglitazone acted slowly to decrease STAT5 RNA and protein levels and prevented the induction of CITED2 and its target genes by imatinib in TKI-resistant chronic-phase CML cells. To assess the efficacy of this combination in humans, pioglitazone was added to imatinib therapy in three patients who had never achieved CMR. In response to dual treatment, all three patients reached CMR, which was maintained for up to 4.7 years after withdrawal of pioglitazone. Early results of a multicenter phase II clinical trial of the imatinib–pioglitazone combination showed sustained CMR in 57% of patients, which was associated with decreased STAT5 expression and CD34+ cell clonogenicity. These results suggest that CML stem cells have a non-oncogene addiction to the PPARγ–STAT5 pathway and that combination therapy with PPARγ agonists and BCR–ABL TKIs may result in cancer eradication in patients with chronic phase CML via gradual erosion of the CML stem cell pool.
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