Nature Medicine
11, 630 - 637 (2005)
Published online: 22 May 2005; | doi:10.1038/nm1253
Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemiaAnders Castor1, 2, Lars Nilsson1, 3, Ingbritt Åstrand-Grundström1, Miranda Buitenhuis4, Carole Ramirez1, Kristina Anderson1, Bodil Strömbeck5, Stanislaw Garwicz2, Albert N Békássy2, Kjeld Schmiegelow6, Birgitte Lausen6, Peter Hokland7, Sören Lehmann8, Gunnar Juliusson3, Bertil Johansson5
& Sten Eirik W Jacobsen1, 31
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, 221 84
Lund, Sweden. 2
Oncology/Hematology Section, Department of Pediatrics, Lund University Hospital, 221 85
Lund, Sweden. 3
Department of Hematology, Lund University Hospital, 221 85
Lund, Sweden. 4
Department of Pulmonary Diseases, University Medical Center, Utrecht, The Netherlands. 5
Department of Clinical Genetics, Lund University Hospital, 221 85
Lund, Sweden. 6
Pediatric Clinic II, Juliane Marie Centre, University Hospital, Rigshospitalet, Copenhagen, Denmark. 7
Department of Hematology, Århus Amtssygehus, Denmark. 8
Department of Hematology, M54 Karolinska Institute, Huddinge Hospital
141 86, Stockholm, Sweden.
Correspondence should be addressed to Sten Eirik W Jacobsen sten.jacobsen@med.lu.seThe 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
