Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists.
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.
CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France.
Stéphane
S
Prost
CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France.
Francis
F
Relouzat
Département de biologie médicale, Hôpital Mignot, F-78150 Le Chesnay, France.
Marc
M
Spentchian
CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France.
Yasmine
Y
Ouzegdouh
CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France.
Joseph
J
Saliba
Unité de Biologie Cellulaire, UMR-S-940 Institut Universitaire d'Hématologie, Hôpital Saint Louis, F-75010 Paris, France.
Gérald
G
Massonnet
Service d'Endocrinologie et de Diabétologie, Hôpital Mignot, F-78150 Le Chesnay, France.
Jean-Paul
JP
Beressi
CIRI, International Center for Infectiology Research, EVIR team, Inserm, U1111, CNRS, UMR5308, Université de Lyon-1, ENS de Lyon, 69007 Lyon, France.|Inserm, U895, Centre de Médecine Moléculaire (C3M), équipe 3, 06204 Nice, France.
Els
E
Verhoeyen
Laboratoire d'hématologie, Centre Hospitalier de Versailles, F-78150 Le Chesnay, France.
Victoria
V
Raggueneau
Unité de Pharmacologie, Service de Biologie Médicale, Centre Hospitalier de Versailles, F-78150 Le Chesnay, France.
Benjamin
B
Maneglier
Service d'Hématologie et d'Oncologie, Hôpital Mignot, Université Versailles Saint-Quentin-en-Yvelines, F-78150 Le Chesnay, France.
Sylvie
S
Castaigne
Unité de Biologie Cellulaire, UMR-S-940 Institut Universitaire d'Hématologie, Hôpital Saint Louis, F-75010 Paris, France.
Christine
C
Chomienne
CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France.|Inserm, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France.
Stany
S
Chrétien
Unité de Biologie Cellulaire, UMR-S-940 Institut Universitaire d'Hématologie, Hôpital Saint Louis, F-75010 Paris, France.|Service d'Hématologie et d'Oncologie, Hôpital Mignot, Université Versailles Saint-Quentin-en-Yvelines, F-78150 Le Chesnay, France.
Philippe
P
Rousselot
CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), F-92265 Fontenay-aux-Roses, France.|Genetics Division, Brigham &Women's Hospital and Harvard Medical School, Boston, Massachussetts 02115, USA.|Hematology Division, Ramathibodi Hospital and Mahidol University, 10400 Bangkok, Thailand.
Philippe
P
Leboulch
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D012097:Repressor Proteins / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D015534:Trans-Activators / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D001549:Benzamides; D000068877:Imatinib Mesylate; D047495:PPAR gamma; D000077205:Pioglitazone; D010879:Piperazines; D011743:Pyrimidines; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D045162:Thiazolidinediones; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1; C486381:CITED2 protein, human