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The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

Author

Listed:
  • Brianna J. Klein

    (University of Colorado School of Medicine)

  • Anagha Deshpande

    (Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

  • Khan L. Cox

    (Ohio State University)

  • Fan Xuan

    (Van Andel Research Institute)

  • Mohamad Zandian

    (University of Colorado School of Medicine)

  • Karina Barbosa

    (Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

  • Sujita Khanal

    (Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

  • Qiong Tong

    (University of Colorado School of Medicine)

  • Yi Zhang

    (University of Colorado School of Medicine)

  • Pan Zhang

    (Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

  • Amit Sinha

    (Basepair Inc)

  • Stefan K. Bohlander

    (University of Auckland)

  • Xiaobing Shi

    (Van Andel Research Institute)

  • Hong Wen

    (Van Andel Research Institute)

  • Michael G. Poirier

    (Ohio State University)

  • Aniruddha J. Deshpande

    (Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

  • Tatiana G. Kutateladze

    (University of Colorado School of Medicine)

Abstract

Chromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

Suggested Citation

  • Brianna J. Klein & Anagha Deshpande & Khan L. Cox & Fan Xuan & Mohamad Zandian & Karina Barbosa & Sujita Khanal & Qiong Tong & Yi Zhang & Pan Zhang & Amit Sinha & Stefan K. Bohlander & Xiaobing Shi & , 2021. "The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24418-9
    DOI: 10.1038/s41467-021-24418-9
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