Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Twin Study
MeSH terms
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ADP-ribosyl Cyclase 1 / analysis
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Acute Disease
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Animals
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Antigens, CD19 / analysis
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Antigens, CD34 / analysis
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Apoptosis
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Bone Marrow Transplantation
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Child, Preschool
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Core Binding Factor Alpha 2 Subunit / analysis
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Core Binding Factor Alpha 2 Subunit / genetics*
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Core Binding Factor Alpha 2 Subunit / physiology
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Diseases in Twins* / genetics
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Diseases in Twins* / metabolism
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Diseases in Twins* / pathology
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Female
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Fetal Blood / transplantation
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Gene Rearrangement, B-Lymphocyte, Heavy Chain
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Humans
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Transplantation
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Neoplastic Stem Cells / pathology
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Oncogene Proteins, Fusion / analysis
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / physiology
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Precursor Cells, B-Lymphoid / chemistry
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Precursor Cells, B-Lymphoid / physiology
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Preleukemia / genetics
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Preleukemia / metabolism
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Preleukemia / pathology*
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Recombination, Genetic
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Transplantation, Heterologous
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Twins, Monozygotic
Substances
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Antigens, CD19
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Antigens, CD34
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Core Binding Factor Alpha 2 Subunit
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Oncogene Proteins, Fusion
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TEL-AML1 fusion protein
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ADP-ribosyl Cyclase 1