630 VOLUME 11 | NUMBER 6 | JUNE 2005 NATURE MEDICINE Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia Anders Castor 1,2 , Lars Nilsson 1,3 , Ingbritt Åstrand-Grundström 1 , Miranda Buitenhuis 4 , Carole Ramirez 1 , Kristina Anderson 1 , Bodil Strömbeck 5 , Stanislaw Garwicz 2 , Albert N Békássy 2 , Kjeld Schmiegelow 6 , Birgitte Lausen 6 , Peter Hokland 7 , Sören Lehmann 8 , Gunnar Juliusson 3 , Bertil Johansson 5 & Sten Eirik W Jacobsen 1,3 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. Cancers and normal stem cells share the unique property of self-renewal. Recently, compelling evidence has emerged for the existence of rare, but distinct, cancer stem cells, in hematologic as well as solid tumors, that are required and sufficient for sustained replenishment of the hierarchy of cells constituting a tumor 1–3 . The close relationship between normal HSCs and leukemic stem cells (LSCs) raises several fundamental questions with considerable tumor biological and clinical implications. The first relates to the cellular ori- gin of LSCs. Clearly, HSCs have extensive capacity for self-renewal and are sustained throughout the life of the organism, and therefore have a much greater chance than more mature cells to accumulate the multiple mutations thought to be required for leukemic transformation. This is particularly relevant for the development of leukemias in short-lived myeloid lineages. In agreement with this, human acute myeloid leuke- mias seem, in most cases, to arise in cells with a HSC phenotype 1 , and in chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS), there is direct evidence for the leukemia-initiating cell repre- senting a multipotent (lymphomyeloid) HSC 4–6 . Determining whether leukemias originate in HSCs could potentially have considerable impact on the efficiency of drug targeting of LSCs, as normal HSCs have been shown to be highly resistant to chemotherapy 7–9 . Another fundamental and unanswered question, potentially related directly to that of the cellular origin of LSCs, is to what extent the nor- mal HSC compartment is affected in leukemia. Recently, HSC niches that tightly control and limit the size of the HSC pool have been identi- fied in the bone marrow 10,11 . Because these niches are restricted in size and seem specific for HSCs and not progenitors, aggressively expanding LSCs derived from normal HSCs could be predicted to competitively reduce the normal HSC pool, whereas progenitor-derived LSCs may compete for other niches and therefore not affect the normal HSC pool to the same extent. In contrast to myeloid progenitors, lymphoid cells can be long lived 12 , making it plausible that ALLs might originate in committed progenitors rather than HSCs, although multiple recent studies have suggested that the primary transformation event in ALLs frequently occurs in the HSC compartment 13–17 . ALL is a heteroge- neous disease, with regard to genetic changes, treatment response and prognosis 18 . The ETV6-RUNX1 (also known as TEL-AML1) fusion, generated by t(12;21)(p13;q22), is believed to be a primary event in the transformation process, necessary but not sufficient for ALL transfor- mation 19,20 . ETV6-RUNX1 fusion–positive ALLs constitute as much as 25–30% of all pediatric ALLs, and have a favorable prognosis (with chemotherapy alone) 21 . The cellular origin of t(12;21) ALL remains unclear. Some studies have suggested the involvement of uncommitted CD34 + CD19 − progenitors in the ETV6-RUNX1 clone 17 , whereas others have suggested that virtually all non-B-cell progenitors in t(12;21) ALLs are ETV6-RUNX1 fusion negative 22 . The minor CD34 + CD38 − 1 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 S.E.W.J. (sten.jacobsen@med.lu.se). Published online 22 May 2005; doi:10.1038/nm1253 ARTICLES © 2005 Nature Publishing Group http://www.nature.com/naturemedicine