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MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment

Oncogene volume 36, pages 3207–3212 (2017)Cite this article

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Abstract

Translocations involving the mixed lineage leukemia-1 are recurrent events in acute leukemia and associate with lymphoid (ALL), myeloid (AML) or mixed lineage (MLL) subtypes. Despite an association with ALL in humans, murine MLL fusion models are persistently restricted to AML. We here explored this issue using an inducible mixed lineage leukemia-eleven nineteen leukemia (MLL-ENL) mouse model. Although multiple progenitor cell types with myeloid potential are potent AML leukemia-initiating cells, also the earliest lymphoid progenitors were capable of initiating AML. This ability to evoke a latent myeloid potential in the earliest lymphoid progenitors was lost upon further lymphoid commitment. At the same time, more downstream/committed lymphoid precursors also failed to initiate lymphoid leukemia. Co-expression of MLL-ENL with a constitutively active RAS allele, the most common co-mutation in MLL fusion leukemias, could influence on both disease latency and lineage assignment of developing leukemia in what appears to be a mutation-order-dependent manner. Finally, CEBPB-mediated transdifferentation of committed and otherwise leukemia-incompetent B-cell progenitors imbued these cells with leukemic competence for AML. Therefore, apart from providing detailed insight into the differential responsiveness of candidate target cells to a first-hit MLL fusion event, our data warrants caution to therapeutic approaches based on the concept of transdifferentiation.

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Acknowledgements

We thank Gerd Sten and Eva Erlandsson for expert technical support. This work was supported by a joint project grant from Knut and Alice Wallenberg Foundation and grants from the Gunnar Nilsson Cancer Foundation, the Swedish Research Council, the Swedish Cancer Society, the Swedish Pediatric Leukemia Foundation and an ERC Consolidator grant 615068 to D.B.

Author contributions

AU designed and performed experiments, analyzed the data and wrote the paper; PS, MD-P, MW and GLN performed experiments; DB conceived and supervised the study, and wrote the paper.

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Authors and Affiliations

  1. Molecular Hematology, Institution for Laboratory Medicine, Lund University, Lund, Sweden

    A Ugale, P Säwén, M Dudenhöffer-Pfeifer, M Wahlestedt, G L Norddahl & D Bryder

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  1. A Ugale
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  2. P Säwén
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  3. M Dudenhöffer-Pfeifer
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  4. M Wahlestedt
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  5. G L Norddahl
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  6. D Bryder
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Correspondence to D Bryder.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Oncogene website

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Ugale, A., Säwén, P., Dudenhöffer-Pfeifer, M. et al. MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment. Oncogene 36, 3207–3212 (2017). https://doi.org/10.1038/onc.2016.470

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  • DOI: https://doi.org/10.1038/onc.2016.470

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