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ACUTE MYELOID LEUKEMIA

Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis

Leukemia volume 36, pages 946–955 (2022)Cite this article

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Abstract

The Switch/Sugar Non-Fermenting (SWI/SNF) nucleosome remodeling complexes play important roles in normal development and in the development of various cancers. Core subunits of the SWI/SNF complexes have been shown to have oncogenic roles in acute myeloid leukemia. However, the roles of the unique targeting subunits, including that of Arid2 and Arid1b, in AML leukemogenesis are not well understood. Here, we used conditional knockout mouse models to elucidate their role in MLL-AF9 leukemogenesis. We uncovered that Arid2 has dual roles; enhancing leukemogenesis when deleted during leukemia initiation and yet is required during leukemia maintenance. Whereas, deleting Arid1b in either phase promotes leukemogenesis. Our integrated analyses of transcriptomics and genomic binding data showed that, globally, Arid2 and Arid1b regulate largely distinct sets of genes at different disease stages, respectively, and in comparison, to each other. Amongst the most highly dysregulated transcription factors upon their loss, Arid2 and Arid1b converged on the regulation of Etv4/Etv5, albeit in an opposing manner while also regulating distinct TFs including Gata2,Tcf4, Six4, Irf4 and Hmgn3. Our data demonstrate the differential roles of SWI/SNF subunits in AML leukemogenesis and emphasize that cellular context and disease stage are key in determining their functions during this process.

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Fig. 1: ARID1B and ARID2 in human AML.
Fig. 2: Arid2 has dual roles in MLL-AF9 leukemogenesis.
Fig. 3: Loss of Arid1b promotes MLL-AF9 leukemogenesis.
Fig. 4: Transcriptomic analysis of Arid2 null leukemia in the VavCre model.
Fig. 5: Transcription regulation by Arid2 in MxCre leukemia.
Fig. 6: Transcription factors regulated by Arid1b in leukemogenesis.

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Acknowledgements

The authors thank Benedetta Bonacci for assistance with cell sorting, Angela Cui for assistance with cloning vectors and Hao Zhu for the gift of the Arid1bfl/fl mouse.

Funding

This work was supported by the Versiti Blood Research Institute Foundation and in part by Institutional Research Grant IRG #16-183-31 from the American Cancer Society and the Medical College of Wisconsin Cancer Center.

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Authors and Affiliations

  1. Blood Research Institute, Versiti, Milwaukee, WI, USA

    Theresa Bluemn, Jesse Schmitz, Yongwei Zheng, Robert Burns, Shikan Zheng, Joshua DeJong, Luke Christiansen, Olivia Arnold, Jesus Izaguirre-Carbonell, Demin Wang & Nan Zhu

  2. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA

    Theresa Bluemn, Luke Christiansen, Olivia Arnold & Nan Zhu

  3. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA

    Demin Wang

  4. Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Aniruddha J. Deshpande

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Contributions

NZ and TB designed the study, and wrote the manuscript; TB, JS, YZ, JD, LC, JI performed research and analyzed data; RB, SZ and OA analyzed RNA-seq and CUT&Tag data; DW and AD provided resources and conceptual input; TB, NZ, AD and DW edited the manuscript with inputs from co-authors.

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Correspondence to Nan Zhu.

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Bluemn, T., Schmitz, J., Zheng, Y. et al. Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis. Leukemia 36, 946–955 (2022). https://doi.org/10.1038/s41375-021-01505-w

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