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Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia

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.

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Figure 1: Absence of multipotent HSC involvement in t(12;21) ALL.
Figure 2: Clonal involvement of the multipotent HSC compartment in P210 BCR-ABL1– but not P190 BCR-ABL1–positive ALLs.
Figure 3: In vitro and in vivo leukemic and normal stem cell activity in t(12;21)- and t(9;22)-positive ALLs.

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Acknowledgements

The assistance of A. Fossum, Z. Ma and G. Gärdebring in cell enrichment and sorting, and L. Wittman in mouse work (all at the Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy) is highly appreciated. We also thank all patients and bone marrow donors for their contributions, and the staff at the Department of Pediatric Oncology/Hematology at Lund University Hospital for valuable contributions. We appreciate discussions with and suggestions of J. Dick and T. Enver. These studies were supported by grants from Avtal om Läkarutbildning och Forskning (Governmental Public Health Grant), the Crafoord Foundation, Georg Danielsson Foundation, Nilsson's Cancer Foundation, Åke Wiberg Foundation, John and Augusta Persson Foundation, John Persson Foundation, Alfred Österlund Foundation, Funds of Lunds Sjukvårdsdistrikt, the Swedish Medical Research Council, Swedish Cancer Society, the Swedish Childhood Cancer Foundation and the Tobias Foundation. The Lund Stem Cell Center is supported by a Swedish Center of Excellence grant in Life Sciences from the Swedish Foundation for Strategic Research. M.B. is supported by the Dutch Cancer Society.

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Correspondence to Sten Eirik W Jacobsen.

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Supplementary information

Supplementary Fig. 1

Lack of myeloid potential of CD19+ cells expressing BCR/ABL (PDF 56 kb)

Supplementary Table 1

Patient characteristics (PDF 26 kb)

Supplementary Methods (PDF 17 kb)

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Castor, A., Nilsson, L., Åstrand-Grundström, I. et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 11, 630–637 (2005). https://doi.org/10.1038/nm1253

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