Abstract
The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-ribosyl Cyclase
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ADP-ribosyl Cyclase 1
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Adult
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Antigens, CD
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Antigens, CD19
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Antigens, CD34
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Child
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Chromosomes, Human, Pair 12
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Chromosomes, Human, Pair 21
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins / physiology
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ETS Translocation Variant 6 Protein
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Flow Cytometry
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / physiology*
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Hematopoietic Stem Cells / physiology*
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Humans
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Membrane Glycoproteins
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Mutation
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Nuclear Proteins / physiology
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Oncogene Proteins, Fusion / physiology
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Phenotype
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / classification*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins c-ets
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Repressor Proteins / physiology
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Translocation, Genetic
Substances
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Antigens, CD
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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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DNA-Binding Proteins
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Membrane Glycoproteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins c-ets
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Repressor Proteins
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TEL-AML1 fusion protein
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Fusion Proteins, bcr-abl
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ADP-ribosyl Cyclase
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CD38 protein, human
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ADP-ribosyl Cyclase 1