Group leader
LIU Zhaoqi is a Principal Investigator in CAS Key Laboratory of Genomic and Precision Medicine in Beijing Institute of Genomics, Chinese Academy of Sciences. He received his PhD degree in applied mathematics from Academy of Mathematics and Systems Science, CAS. Between 2015 and 2018, he was a Postdoctoral Research Scientist in the Department of Biomedical Informatics at Columbia University. From 2018, he was promoted to an Associate Research Scientist. He joined Beijing Institute of Genomics, CAS in October 2020, focusing on the application of data science technology in cancer genomics and pharmacogenomics.
Introduction
1) Aberrant RNA splicing
RNA splicing is a critical regulator of gene expression and mediator of proteome diversity. The most commonly reported spliceosomal mutations converged to genes including: SF3B1, U2AF1, SRSF2 and ZRSR2 (loss of function), which have been repeatedly identified in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), chronic lymphocytic leukemia as well as other myeloid neoplasms. While alterations in splicing factor genes have been suggested to promote tumorigenesis, the discovery of recurrent, high frequency change-of-function mutations in RNA splicing factors (SF) in human cancers underscored a central role for altered splicing in hematologic malignancies and solid tumors. To study the effect of SF mutations on tumorigenesis, a few challenging steps are necessary: a) Rapid identification and accurate quantification of cancer-specific aberrant RNA splicing genome-widely, b) Determining the major changes of downstream cellular processes under splicing dysregulation in a systematic way, and c) Understanding the molecular mechanisms of tumorigenesis and fast translation to potential therapeutic strategy. All these steps require extensive computational efforts. Our lab will integrate knowledges in cancer genomics, systems biology, machine learning and computer science to address these challenging difficulties.
2) Precision Medicine
Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive intertumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Immunotherapies has proven to have improved objective response in tumors with high nonsynonymous mutation burden. T cell recognition of cancers relies upon presentation of tumor-specific antigens on MHC molecules, which generated by nonsynonymous mutations. However, recent studies suggested that tumor-specific alternative splicing events are far more abundant than the somatic single-nucleotide variants, and that peptides translated from intron-containing mRNAs are a unique class of neo-antigens in AML and other malignancies. In addition, spliceosome targeted therapies lead to global mis-processing of RNA and subsequent aberrant translation of intron encoded peptides. In this setting, we hypothesize that widespread accumulation of intron-encoded peptides due to RNA mis-splicing, would results in production of neo-antigens that can be targeted immunologically. We will collaborate with clinicians and pharmacists, and apply our expertise in computational biology to address this challenge.
Selected Publications
1. Liu, Z.,* Yoshimi, A.,* Wang, J., Cho, H., Lee, S.C.W., Ki, M., Bitner, L., Chu, T., Shah, H., Liu, B. and Mato, A.R., 2020. Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization. Cancer Discovery, doi:10.1158/2159-8290.CD-19-1330
2. Liu, Z., Rabadan, R., Computing the Role of Alternative Splicing in Cancer. Trends in Cancer, (in press)
3. Liu, Z.,* Zhang, J.,* Sun, Y., Perea-Chamblee, T., Manley, J., Rabadan, R., 2020. Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation. Proceedings of the National Academy of Sciences USA, doi:10.1073/pnas.1922622117
4. Liu, Z., Filip, I., Gomez, K., Engelbrecht, D., Meer, S., Laloo, P., Patel, P., Perner, Y., Zhao, J. and Wang, J., Genomic characterization of HIV-associated plasmablastic lymphoma identifies pervasive mutations in the JAK-STAT pathway. Blood Cancer Discovery, doi:10.1158/2643-3230.BCD-20-0051
5. Lee, J.K.,* Liu, Z.,* Sa, J.K.,* Shin, S.,* Wang, J.,* Bordyuh, M., Cho, H.J., Elliott, O., Chu, T., Choi, S.W. and Rosenbloom, D.I., 2018. Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy. Nature genetics, 50(10), pp.1399-1411.
6. Arnes, L.,* Liu, Z.,* Wang, J.,* Maurer, H.C., Sagalovskiy, I., Sanchez-Martin, M., Bommakanti, N., Garofalo, D.C., Balderes, D.A., Sussel, L. and Olive, K.P., 2019. Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma. Gut, 68(3), pp.499-511.
7. Liu, B.,* Liu, Z.,* Ki, M., Erickson, C., Reis-Filho, J., Durham, B., Sun, Y., Rabadan, R. and Abdel-Wahab, O., Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis. The Journal of Clinical Investigation (2020): 10.1172/JCI138315.
