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

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, Hong Wen, Michael G. Poirier, Aniruddha J. Deshpande () and Tatiana G. Kutateladze ()
Additional contact information
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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-24418-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24418-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-24418-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().