PDX models reflect the proteome landscape of pediatric acute lymphoblastic leukemia but divert in select pathways

Journal of Experimental & Clinical Cancer Research

Janice Tsui¹  Enes K. Ergin¹  Samuel S. H. Weng¹  Anuli C. Uzozie¹  Philipp F. Lange¹  Lorenz Nierves¹  Theodore G. Smith¹  Christopher A. Maxwell²  Amanda Lorentzian²  Nina Rolf²  C. James Lim²  Gregor S. D. Reid² 

[1]Department of Pathology, University of British Columbia

[2]Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute

关键词: Leukemia;    Xenograft;    Proteolysis;    Proteome;    N termini;    Phosphorylation;   

DOI  :  10.1186/s13046-021-01835-8

来源: DOAJ

【 摘 要 】

Abstract Background Murine xenografts of pediatric leukemia accurately recapitulate genomic aberrations. How this translates to the functional capacity of cells remains unclear. Here, we studied global protein abundance, phosphorylation, and protein maturation by proteolytic processing in 11 pediatric B- and T- cell ALL patients and 19 corresponding xenografts. Methods Xenograft models were generated for each pediatric patient leukemia. Mass spectrometry-based methods were used to investigate global protein abundance, protein phosphorylation, and limited proteolysis in paired patient and xenografted pediatric acute B- and T- cell lymphocytic leukemia, as well as in pediatric leukemia cell lines. Targeted next-generation sequencing was utilized to examine genetic abnormalities in patients and in corresponding xenografts. Bioinformatic and statistical analysis were performed to identify functional mechanisms associated with proteins and protein post-translational modifications. Results Overall, we found xenograft proteomes to be most equivalent with their patient of origin. Protein level differences that stratified disease subtypes at diagnostic and relapse stages were largely recapitulated in xenografts. As expected, PDXs lacked multiple human leukocyte antigens and complement proteins. We found increased expression of cell cycle proteins indicating a high proliferative capacity of xenografted cells. Structural genomic changes and mutations were reflected at the protein level in patients. In contrast, the post-translational modification landscape was shaped by leukemia type and host and only to a limited degree by the patient of origin. Of 201 known pediatric oncogenic drivers and drug-targetable proteins, the KMT2 protein family showed consistently high variability between patient and corresponding xenografts. Comprehensive N terminomics revealed deregulated proteolytic processing in leukemic cells, in particular from caspase-driven cleavages found in patient cells. Conclusion Genomic and host factors shape protein and post-translational modification landscapes differently. This study highlights select areas of diverging biology while confirming murine patient-derived xenografts as a generally accurate model system.

【 授权许可】

Unknown