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Molecular targets for therapy

Constitutive activation of nuclear factor kappa B-inducing kinase counteracts apoptosis in cells with rearranged mixed lineage leukemia gene

Leukemia volume 32, pages 2498–2501 (2018)Cite this article

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Chromosomal rearrangements and translocations of the mixed-lineage leukemia 1 (MLL1, 11q23) gene are responsible for 5–10% of childhood and adult acute myeloid leukemia cases [1]. A frequent alteration of the MLL gene are reciprocal translocations giving rise to MLL fusion oncoprotein (Supplementary Figure S1a) that exhibit a loss of MLL's H3K4 methyltransferase activity affecting histone modifications and thereby gene transcription [1]. One prominent feature of MLL-rearranged leukemias is the upregulation of the later HOX cluster genes and MEIS1 genes, which expression is crucial in developmental processes like hematopoiesis [1]. In general, the prognosis for these patients is very poor compared to other leukemias [2]. A recent study demonstrated that the canonical nuclear factor-κB (NF-κB) signaling contributes to MLL fusion protein-dependent ectopic HOX expression, promotion of proliferation, survival, and differentiation arrest of leukemic cells [3]. Remarkably, some hematological cancers such as multiple myeloma, T-cell leukemia, or Hodgkin Reed-Sternberg cells show an increased activity of the canonical NF-κB, which might, in some cases, be accompanied by a constitutively active non-canonical NF-κB pathway [4,5,6]. Due to the discrete activation of the non-canonical NF-κB pathway by a subset of TNF family receptors, it constitutes an attractive therapeutic target [7]. Therefore, we investigated for the first time the contribution of the non-canonical NF-κB signaling to the survival of MLL-rearranged leukemia cells after chemotherapeutic drug treatment.

To overcome the inherent genetic heterogeneity of MLL patient material, we used primary human CD34+ cord blood cell line transduced with MLL-AF9 fusion cDNA [8]. As reported by Wei et al. [8], this modified cell line displays a strong similarity to the gene expression profile of cells with MLL-AF9 fusion obtained from patients with AML. To fully assess the non-canonical NF-κB activity in AML with MLL gene rearrangement, we compared transduced cells to closely related, yet non-transduced counterparts, the generally accepted human CD34+ blood stem/progenitor cells [9]. In addition, CD34+ MLL-AF9 cells were compared to another primary human CD34+ cord blood cell line carrying an AML1-ETO rearrangement [10] to evaluate a different type of gene translocation driving AML, but with a better prognosis than MLL-AF9.

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Acknowledgements

The authors kindly thank Prof. J.C. Mulloy and Dr. M. Wunderlich for providing CD34+MLL-AF9 and CD34+AML1-ETO cells, respectively. This work was supported by grants from the German Federal Ministry of Education and Research (e:Bio, 031A304) and the Ministry of Economy, Research and Digitalization of Saxony-Anhalt (support from the European Fund for Regional Development (EFRD) (ZS/2016/04/78155)) to MN.

Author contributions:

MS-T and MN designed the study. MS-T and GM performed experiments. MS-T, MHF, and MN analyzed and interpreted the data. MS-T, MHF, GM, and MN wrote and revised the manuscript.

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  1. Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany

    Maja Studencka-Turski, Gunter Maubach, Michael Hartmut Feige & Michael Naumann

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  1. Maja Studencka-Turski
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Correspondence to Michael Naumann.

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Studencka-Turski, M., Maubach, G., Feige, M.H. et al. Constitutive activation of nuclear factor kappa B-inducing kinase counteracts apoptosis in cells with rearranged mixed lineage leukemia gene. Leukemia 32, 2498–2501 (2018). https://doi.org/10.1038/s41375-018-0128-7

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