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Acute Leukemias

Cell of origin determines clinically relevant subtypes of MLL-rearranged AML

Leukemia volume 27, pages 852–860 (2013)Cite this article

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Abstract

Mixed lineage leukemia (MLL)-fusion proteins can induce acute myeloid leukemias (AMLs) from either hematopoietic stem cells (HSCs) or granulocyte–macrophage progenitors (GMPs), but it remains unclear whether the cell of origin influences the biology of the resultant leukemia. MLL-AF9-transduced single HSCs or GMPs could be continuously replated, but HSC-derived clones were more likely than GMP-derived clones to initiate AML in mice. Leukemia stem cells derived from either HSCs or GMPs had a similar immunophenotype consistent with a maturing myeloid cell (LGMP). Gene expression analyses demonstrated that LGMP inherited gene expression programs from the cell of origin including high-level Evi-1 expression in HSC-derived LGMP. The gene expression signature of LGMP derived from HSCs was enriched in poor prognosis human MLL-rearranged AML in three independent data sets. Moreover, global 5′-mC levels were elevated in HSC-derived leukemias as compared with GMP-derived leukemias. This mirrored a difference seen in 5′-mC between MLL-rearranged human leukemias that are either EVI1 positive or EVI1 negative. Finally, HSC-derived leukemias were more resistant to chemotherapy than GMP-derived leukemias. These data demonstrate that the cell of origin influences the gene expression profile, the epigenetic state and the drug response in AML, and that these differences can account for clinical heterogeneity within a molecularly defined group of leukemias.

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Acknowledgements

We thank Renee Wright for technical help and Megan Smith for administrative assistance. This work was supported in part by the National Cancer Institute (5P01CA66996), the Leukemia and Lymphoma Society, the American Cancer Society and the Harvard Stem Cell Institute, and the German Research Foundation (DFG Heisenberg-Stipendium BU 1339/3-1).

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Authors and Affiliations

  1. Division of Hematology/Oncology, Children’s Hospital, Boston, MA, USA

    A V Krivtsov, A U Sinha, M C Stubbs, Z Feng & S A Armstrong

  2. Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    A V Krivtsov, A U Sinha, Z Feng & S A Armstrong

  3. Department of Pediatrics and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A V Krivtsov, A U Sinha & S A Armstrong

  4. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI

    M E Figueroa

  5. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    M E Figueroa & A M Melnick

  6. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    P J M Valk & R Delwel

  7. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    K Döhner & L Bullinger

  8. Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA

    A L Kung

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Krivtsov, A., Figueroa, M., Sinha, A. et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia 27, 852–860 (2013). https://doi.org/10.1038/leu.2012.363

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