Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists

Abstract

Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.

Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML

“…33,34 However, the LSC population is heterogeneous, consisting of a mixture of leukemic cells with differences in TKI sensitivity as well as residual healthy stem cells and progenitors. 10,31,35 Single-cell gene expression analysis offers the possibility to identify distinct subpopulations within the stem cell population in CML while directly discriminating between leukemic and normal cells based on BCR-ABL expression.…”

Balaglitazone reverses P-glycoprotein-mediated multidrug resistance via upregulation of PTEN in a PPARγ-dependent manner in leukemia cells

“…23,24 Several recent studies have reported that targeting PPARγ might be an effective adjunct therapy in leukemia. In a very recent study, Prost et al 25 demonstrated that PPARγ agonists synergistically reduced the number of colony-forming cells in patients with chronic myeloid leukemia (CML). Lin et al 26 showed that the expression levels of ABC transporters and PTEN in tumor cells are important determinants of combination therapy efficacy and proposed that PTEN status of the tumor should be taken into account during the analysis of the clinical trials.…”

Enhancing human cord blood hematopoietic stem cell engraftment by targeting nuclear hormone receptors

“…It is unknown if leukemia cell growth is dependent on glucose metabolism activated by suppressing FBP1, and if inhibition of FBP1 impairs mitochondria metabolism in leukemia. PPARγ agonist glitazones decreases expression of STAT5 target genes, HIF2α and CITED2 , and disrupts quiescence and stemness of chronic myeloid leukaemia (CML) stem cells LSCs [63]. Further studies are needed to determine if PPARγ activation impairs glucose metabolism by increasing FBP1 expression in CML LSCs.…”