PML targeting eradicates quiescent leukaemia-initiating cells.
The existence of a small population of 'cancer-initiating cells' responsible for tumour maintenance has been firmly demonstrated in leukaemia. This concept is currently being tested in solid tumours. Leukaemia-initiating cells, particularly those that are in a quiescent state, are thought to be resistant to chemotherapy and targeted therapies, resulting in disease relapse. Chronic myeloid leukaemia is a paradigmatic haematopoietic stem cell disease in which the leukaemia-initiating-cell pool is not eradicated by current therapy, leading to disease relapse on drug discontinuation. Here we define the critical role of the promyelocytic leukaemia protein (PML) tumour suppressor in haematopoietic stem cell maintenance, and present a new therapeutic approach for targeting quiescent leukaemia-initiating cells and possibly cancer-initiating cells by pharmacological inhibition of PML.
Ito
Keisuke
K
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Harvard Medical School, New Research Building, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Bernardi
Rosa
R
Morotti
Alessandro
A
Matsuoka
Sahoko
S
Saglio
Giuseppe
G
Ikeda
Yasuo
Y
Rosenblatt
Jacalyn
J
Avigan
David E
DE
Teruya-Feldstein
Julie
J
Pandolfi
Pier Paolo
PP
D000328:Adult; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D018920:Coculture Techniques; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use; D000071156:Promyelocytic Leukemia Protein; D012008:Recurrence; D012038:Regeneration; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D000077237:Arsenic Trioxide