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Therapeutic targeting potential of chromatin-associated proteins in MLL-rearranged acute leukemia

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Abstract

Background

Acute leukemias (AL) with a Mixed Lineage Leukemia (MLL) gene rearrangement (MLLr) represent a group of leukemic entities conferring intermediate to adverse prognoses. Multiple chromatin-associated proteins have been shown to play essential roles during the genesis of MLLr AL. Some chromatin-associated proteins function as negative regulators of MLLr AL whereas others are required for leukemic initiation or maintenance - the latter group constituting potential therapeutic targets. Most of the identified proteins have been functionally analyzed using experimental models with human/murine normal cells transformed by MLL-AF9 or other MLL fusion products, which may recapitulate most but not all aspects of human AML, such as immune system interactions – features of which the importance is rapidly emerging.

Conclusions

Here, we review chromatin-associated proteins fundamental to MLLr AL development, highlighting those with targeting potential by small molecule inhibitors. In particular, we focus on synthetic targeting of multiple chromatin-associated proteins, a strategy that shows superior therapeutic efficacy and offers hope for overcoming drug resistance.

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Funding

Xin Xu was funded by the National Natural Science Foundation of China (NSFC; grant # 81370628 and # 81570157), the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry, Shandong Provincial Natural Science Foundation, China (grant # ZR2015CL023), and the Shandong Province Higher Educational Science and Technology Program (J16LL54).

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Authors and Affiliations

  1. Laboratory for Stem Cell and Regenerative Medicine, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, 261053, People’s Republic of China

    Xin Xu

  2. College of Bioscience and Technology, Weifang Medical University, #21406 Basic Laboratory Building, 7166 Baotongxi Street, Weifang, Shandong Province, 261053, People’s Republic of China

    Xin Xu

  3. Institute of Pathology, University Medicine Rostock, Strempelstrasse 14, 18055, Rostock, Germany

    Björn Schneider

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  1. Xin Xu
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Correspondence to Björn Schneider.

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Xu, X., Schneider, B. Therapeutic targeting potential of chromatin-associated proteins in MLL-rearranged acute leukemia. Cell Oncol. 42, 117–130 (2019). https://doi.org/10.1007/s13402-018-0414-4

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