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LEDGF/p75-mediated chemoresistance of mixed-lineage leukemia involves cell survival pathways and super enhancer activators

Cancer Gene Therapy volume 29, pages 133–140 (2022)Cite this article

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Abstract

MLL is an aggressive subtype of leukemia with a poor prognosis that mostly affects pediatric patients. MLL-rearranged fusion proteins (MLLr) induce aberrant target gene expression resulting in leukemogenesis. MLL and its fusions are tethered to chromatin by LEDGF/p75, a transcriptional co-activator that specifically recognizes H3K36me2/3. LEDGF/p75 is ubiquitously expressed and associated with regulation of gene expression, autoimmune responses, and HIV replication. LEDGF/p75 was proven to be essential for leukemogenesis in MLL. Apart from MLL, LEDGF/p75 has been linked to lung, breast, and prostate cancer. Intriguingly, LEDGF/p75 interacts with Med-1, which co-localizes with BRD4. Both are known as co-activators of super-enhancers. Here, we describe LEDGF/p75-dependent chemoresistance of MLLr cell lines. Investigation of the underlying mechanism revealed a role of LEDGF/p75 in the cell cycle and in survival pathways and showed that LEDGF/p75 protects against apoptosis during chemotherapy. Remarkably, LEDGF/p75 levels also affected expression of BRD4 and Med1. Altogether, our data suggest a role of LEDGF/p75 in cancer survival, stem cell renewal, and activation of nuclear super enhancers.

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Fig. 1: LEDGF/p75 is involved in chemoresistance and cell cycle regulation in MLL-AF9 cell lines.
Fig. 2: LEDGF/p75 regulates the sphingosine-1P survival pathway in MLL-AF9 cell lines.
Fig. 3: LEDGF/p75 regulates super enhancers in MLL-AF9 cell lines.

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Acknowledgements

We gratefully acknowledge Martine Michiels for the technical support, the Genomics core facility for library preparation, sequencing and data normalization, the FACS core facility for the acquisition of the samples.

Funding

The work was supported by the FWO (Grant G099018N (3M180106) to ZD). SVB is a recipient of a FWO PhD fellowship and MSC of a FWO postdoctoral fellowship.

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Authors and Affiliations

  1. Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Flanders, Belgium

    Alessandro Canella, Siska Van Belle, Tine Brouns, Marianne S. Carlon, Frauke Christ & Zeger Debyser

  2. Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Giovanni Nigita

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  1. Alessandro Canella
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  2. Siska Van Belle
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Contributions

AC, SVB, TB, and MSC performed experiments. AC contributed substantially to the design of experiments, and analysis of data. GN contributed to the RNA-seq data analysis and interpretation. AC, FC, and ZD interpreted the data and wrote the manuscript. All the authors were involved in the final editing and ZD approved the final manuscript.

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Correspondence to Alessandro Canella or Zeger Debyser.

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Canella, A., Van Belle, S., Brouns, T. et al. LEDGF/p75-mediated chemoresistance of mixed-lineage leukemia involves cell survival pathways and super enhancer activators. Cancer Gene Ther 29, 133–140 (2022). https://doi.org/10.1038/s41417-021-00319-3

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