Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia.
Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, we establish the lineal relationship between these "cancer-propagating" cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1-transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties.
Hong
Dengli
D
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
Gupta
Rajeev
R
Ancliff
Philip
P
Atzberger
Ann
A
Brown
John
J
Soneji
Shamit
S
Green
Joanne
J
Colman
Sue
S
Piacibello
Wanda
W
Buckle
Veronica
V
Tsuzuki
Shinobu
S
Greaves
Mel
M
Enver
Tariq
T
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000208:Acute Disease; D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D004200:Diseases in Twins / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005312:Fetal Blood / Q000637:transplantation; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D054448:Precursor Cells, B-Lymphoid / Q000737:chemistry / Q000502:physiology; D011289:Preleukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011995:Recombination, Genetic; D014183:Transplantation, Heterologous; D014430:Twins, Monozygotic; D000097764:ETS Translocation Variant 6 Protein
D051997:ADP-ribosyl Cyclase 1; D018941:Antigens, CD19; D018952:Antigens, CD34; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein