The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations
Brianna J. Klein, Anagha Deshpande, Khan L. Cox, Xuan Fan, 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, Tatiana G. Kutateladze, Aniruddha J. Deshpande, Tatiana G. Kutateladze
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 (AF10 PZP ), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10 PZP 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 AF10 PZP 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. AF10 PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10 PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10 PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10 PZP -dependent CALM-AF10-mediated leukemogenesis.