Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia.
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.
Castor
Anders
A
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, 221 84 Lund, Sweden.
Nilsson
Lars
L
Astrand-Grundström
Ingbritt
I
Buitenhuis
Miranda
M
Ramirez
Carole
C
Anderson
Kristina
K
Strömbeck
Bodil
B
Garwicz
Stanislaw
S
Békássy
Albert N
AN
Schmiegelow
Kjeld
K
Lausen
Birgitte
B
Hokland
Peter
P
Lehmann
Sören
S
Juliusson
Gunnar
G
Johansson
Bertil
B
Jacobsen
Sten Eirik W
SE
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D015703:Antigens, CD; D018941:Antigens, CD19; D018952:Antigens, CD34; D002648:Child; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000502:physiology; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins / Q000502:physiology; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D018941:Antigens, CD19; D018952:Antigens, CD34; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C102421:TEL-AML1 fusion protein; C498154:CD38 protein, human