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162 results on '"Wan, Youzhong"'

3. A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion

Author

Yin, Shanye, Gambe, Rutendo G, Sun, Jing, Martinez, Aina Zurita, Cartun, Zachary J, Regis, Fara Faye D, Wan, Youzhong, Fan, Jean, Brooks, Angela N, Herman, Sarah EM, Hacken, Elisa ten, Taylor-Weiner, Amaro, Rassenti, Laura Z, Ghia, Emanuela M, Kipps, Thomas J, Obeng, Esther A, Cibulskis, Carrie L, Neuberg, Donna, Campagna, Dean R, Fleming, Mark D, Ebert, Benjamin L, Wiestner, Adrian, Leshchiner, Ignaty, DeCaprio, James A, Getz, Gad, Reed, Robin, Carrasco, Ruben D, Wu, Catherine J, and Wang, Lili

Subjects
Rare Diseases, Lymphoma, Cancer, Genetics, Hematology, 2.1 Biological and endogenous factors, Aetiology, Adenine, Agammaglobulinaemia Tyrosine Kinase, Alternative Splicing, Animals, Antineoplastic Agents, Ataxia Telangiectasia Mutated Proteins, B-Lymphocytes, Cellular Senescence, DNA Damage, Gene Deletion, Genetic Predisposition to Disease, Genomic Instability, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Mutation, Neoplasms, Experimental, Phenotype, Phosphoproteins, Piperidines, Protein Kinase Inhibitors, Pyrazoles, Pyrimidines, RNA Splicing Factors, Receptors, Antigen, B-Cell, Signal Transduction, Tumor Cells, Cultured, ATM, BCR signaling, CLL, SF3B1, murine model, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

SF3B1 is recurrently mutated in chronic lymphocytic leukemia (CLL), but its role in the pathogenesis of CLL remains elusive. Here, we show that conditional expression of Sf3b1-K700E mutation in mouse B cells disrupts pre-mRNA splicing, alters cell development, and induces a state of cellular senescence. Combination with Atm deletion leads to the overcoming of cellular senescence and the development of CLL-like disease in elderly mice. These CLL-like cells show genome instability and dysregulation of multiple CLL-associated cellular processes, including deregulated B cell receptor signaling, which we also identified in human CLL cases. Notably, human CLLs harboring SF3B1 mutations exhibit altered response to BTK inhibition. Our murine model of CLL thus provides insights into human CLL disease mechanisms and treatment.

Published
2019

4. Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Author

Wang, Lili, Brooks, Angela N, Fan, Jean, Wan, Youzhong, Gambe, Rutendo, Li, Shuqiang, Hergert, Sarah, Yin, Shanye, Freeman, Samuel S, Levin, Joshua Z, Fan, Lin, Seiler, Michael, Buonamici, Silvia, Smith, Peter G, Chau, Kevin F, Cibulskis, Carrie L, Zhang, Wandi, Rassenti, Laura Z, Ghia, Emanuela M, Kipps, Thomas J, Fernandes, Stacey, Bloch, Donald B, Kotliar, Dylan, Landau, Dan A, Shukla, Sachet A, Aster, Jon C, Reed, Robin, DeLuca, David S, Brown, Jennifer R, Neuberg, Donna, Getz, Gad, Livak, Kenneth J, Meyerson, Matthew M, Kharchenko, Peter V, and Wu, Catherine J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Lymphoma, Genetics, Clinical Research, Cancer, Rare Diseases, Hematology, 2.1 Biological and endogenous factors, Aetiology, Alternative Splicing, Cell Line, Tumor, Dishevelled Proteins, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Phosphoproteins, RNA Splicing Factors, Receptors, Notch, Signal Transduction, CLL, Notch signaling, RNA sequencing, SF3B1, alternative splicing, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.

Published
2016

5. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

Author

Burger, Jan A, Landau, Dan A, Taylor-Weiner, Amaro, Bozic, Ivana, Zhang, Huidan, Sarosiek, Kristopher, Wang, Lili, Stewart, Chip, Fan, Jean, Hoellenriegel, Julia, Sivina, Mariela, Dubuc, Adrian M, Fraser, Cameron, Han, Yulong, Li, Shuqiang, Livak, Kenneth J, Zou, Lihua, Wan, Youzhong, Konoplev, Sergej, Sougnez, Carrie, Brown, Jennifer R, Abruzzo, Lynne V, Carter, Scott L, Keating, Michael J, Davids, Matthew S, Wierda, William G, Cibulskis, Kristian, Zenz, Thorsten, Werner, Lillian, Dal Cin, Paola, Kharchencko, Peter, Neuberg, Donna, Kantarjian, Hagop, Lander, Eric, Gabriel, Stacey, O'Brien, Susan, Letai, Anthony, Weitz, David A, Nowak, Martin A, Getz, Gad, and Wu, Catherine J

Subjects
Humans, Neoplasm Recurrence, Local, Pyrazoles, Pyrimidines, Apoptosis, Drug Resistance, Neoplasm, Mutation, Adult, Aged, 80 and over, Middle Aged, Female, Male, Protein-Tyrosine Kinases, Leukemia, Lymphocytic, Chronic, B-Cell, Cell Transdifferentiation, Histiocytic Sarcoma, Selection, Genetic, Clonal Evolution, Agammaglobulinaemia Tyrosine Kinase, Aged, and over, Drug Resistance, Neoplasm, Leukemia, Lymphocytic, Chronic, B-Cell, Neoplasm Recurrence, Local, Selection, Genetic
Abstract

Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

Published
2016

21. Mutagenesis by reversible promoter insertion to study the activation of NF-[kappa]

Author

Kandel, Eugene S., Lu, Tao, Wan, Youzhong, Agarwal, Mukesh K., Jackson, Mark W., and Stark, George R.

Subjects
DNA -- Research, Cells -- Research, Science and technology
Abstract

Genetic dissection of signaling pathways in mammalian cells involves screening or selecting phenotypic mutants obtained by a variety of techniques. Limitations in current methods include inadequate genome coverage and difficulty in validating the link between mutation and phenotype. We describe an improved method for insertional mutagenesis with retroviral vectors and show that the ability to induce mutations increases greatly if a randomly inserted promoter directs transcription into the host DNA. The mutant phenotype is due to the expression of a hybrid transcript derived from the vector and the insertion site. Because other alleles of the affected gene remain intact, the phenotype is dominant, but is reversible by inactivating the promoter, for example, by site-specific recombination. Importantly, in mutant clones with multiple inserts, limited excision yields progeny with different patterns of inserts remaining. Characterizing these progeny allows the mutant phenotype to be associated with a specific target gene. Relative simplicity and robust target validation make the method suitable for a broad range of applications. We have used this technique to search for proteins that regulate NF-[kappa]B- dependent signaling in human cells. Two validated targets are the re/A gene, which codes for the NF-[kappa]B p65 subunit, and the NF-[kappa]B regulator act1. Overexpression of the corresponding proteins, caused by insertion of a promoter into the first intron of each gene, leads to NF-[kappa]B-dependent secretion of factors that activate NF-[kappa]B through cell-surface receptors, establishing an autocrine loop. Act1 | forward genetics | p65 RelA

Published
2005

25. SF3B1 and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia

Author

Wang, Lili, Lawrence, Michael S., Wan, Youzhong, Stojanov, Petar, Sougnez, Carrie, Stevenson, Kristen, Werner, Lillian, Sivachenko, Andrey, DeLuca, David S., Zhang, Li, Zhang, Wandi, Vartanov, Alexander R., Fernandes, Stacey M., Goldstein, Natalie R., Folco, Eric G., Cibulskis, Kristian, Tesar, Bethany, Sievers, Quinlan L., Shefler, Erica, Gabriel, Stacey, Hacohen, Nir, Reed, Robin, Meyerson, Matthew, Golub, Todd R., Lander, Eric S., Neuberg, Donna, Brown, Jennifer R., Getz, Gad, and Wu, Catherine J.

Published
2011

27. E239K mutation abolishes the suppressive effects of lysine‐specific demethylase 1 on migration and invasion of MCF7 cells.

Author

Zhang, Yu, Wu, Tong, Zhao, Bo, Liu, Ziyu, Qian, Rui, Zhang, Jing, Shi, Yueru, Wan, Youzhong, Li, Zhe, and Hu, Xin

Abstract

Lysine‐specific demethylase 1 (LSD1) is an important histone demethylase that mediates epithelial to mesenchymal transition (EMT). The E239K mutation of LSD1 was identified in a luminal breast cancer patient from the COSMIC Breast Cancer dataset. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with WT LSD1, but not E239K mutated LSD1, suppressed the invasion and migration of the LSD1 knockdown cells, indicating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion and migration of MCF7 cells. Further analysis showed that the E239K mutation abolished LSD1‐mediated invasion and migration of MCF7 cells through downregulation of estrogen receptor α (ERα). Most importantly, the E239K mutation disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of the ERα gene; the reduced enrichment of LSD1 at the promoter region of the ERα gene caused enhanced histone H3K9 methylation, which subsequently suppressed the transcription of the ERα gene. In summary, the E239K mutation abolishes the suppressive function of LSD1 on migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3. [ABSTRACT FROM AUTHOR]

Published
2022
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29. Extracts and components of

Author

Zhang, Yu, Wan, Youzhong, Huo, Bo, Li, Boyuan, Jin, Yue, and Hu, Xin

Subjects
breast cancer, Ficus carica, MDA-MB-231, migration, OncoTargets and Therapy, Original Research
Abstract

Yu Zhang,1 Youzhong Wan,1,2 Bo Huo,1 Boyuan Li,1 Yue Jin,1 Xin Hu1 1School of Life Sciences, Jilin University, Changchun, Jilin, People’s Republic of China; 2National Engineering Laboratory of AIDS Vaccine, Jilin University, Changchun, Jilin, People’s Republic of China Background: Products from Ficus carica have been used in traditional medicine to treat many diseases. This study aimed to analyze anticancer effects of extracts of F. carica leaves on the triple-negative breast cancer cell line MDA-MB-231. Materials and methods: The human breast cancer cell line MDA-MB-231 was used to evaluate effects of F. carica extracts. Effects of F. carica on cell viability were evaluated using MTT assays. Cell-cycle distribution was examined using cell-cycle analysis. Wound-healing assays were used to evaluate migration of MDA-MB-231. Quantitative reverse-transcription polymerase chain reaction was used to detect levels of Bax, p53, p21, GATA3, ELF5, cyclin-dependent kinases, MMP2, and tissue inhibitors of metalloproteinase. Results: We investigated the mechanism of anti-growth effects, and found that the expressions of genes that promote apoptosis were increased. In addition, the treated cells illustrated increased portion at S phase and changed expression of cyclin-dependent kinases, demonstrating cell-cycle arrest at the S phase. Furthermore, treated cells showed decreased cell mobility, which is essential for metastasis. Two of the active components of F. carica leaves, bergapten and psoralen, had similar anticancer effects as F. carica leaf extracts, indicating that these two components might play important roles in anticancer effects of F. carica leaves. Conclusion: Our findings suggest that F. carica leaves might be a good source to develop drugs for suppressing cancer-cell growth and migration to treat triple-negative breast cancers. Keywords: Ficus carica, breast cancer, MDA-MB-231, migration

Published
2018

31. A Pandas complex adapted for piRNA-guided transposon silencing

Author

Zhao, Kang, primary, Cheng, Sha, additional, Miao, Na, additional, Xu, Ping, additional, Lu, Xiaohua, additional, Zhang, Yuhan, additional, Wang, Ming, additional, Ouyang, Xuan, additional, Yuan, Xun, additional, Liu, Weiwei, additional, Lu, Xin, additional, Zhou, Peng, additional, Gu, Jiaqi, additional, Zhang, Yiqun, additional, Qiu, Ding, additional, Jin, Zhaohui, additional, Su, Chen, additional, Peng, Chao, additional, Wang, Jian-Hua, additional, Dong, Meng-Qiu, additional, Wan, Youzhong, additional, Ma, Jinbiao, additional, Cheng, Hong, additional, Huang, Ying, additional, and Yu, Yang, additional

Published
2019
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34. Extracts and components of Ficus carica leaves suppress survival, cell cycle, and migration of triple-negative breast cancer MDA-MB-231 cells

Author

Zhang,Yu, Wan,Youzhong, Huo,Bo, Li,Boyuan, Jin,Yue, Hu,Xin, Zhang,Yu, Wan,Youzhong, Huo,Bo, Li,Boyuan, Jin,Yue, and Hu,Xin

Abstract

Yu Zhang,1 Youzhong Wan,1,2 Bo Huo,1 Boyuan Li,1 Yue Jin,1 Xin Hu1 1School of Life Sciences, Jilin University, Changchun, Jilin, People’s Republic of China; 2National Engineering Laboratory of AIDS Vaccine, Jilin University, Changchun, Jilin, People’s Republic of China Background: Products from Ficus carica have been used in traditional medicine to treat many diseases. This study aimed to analyze anticancer effects of extracts of F. carica leaves on the triple-negative breast cancer cell line MDA-MB-231. Materials and methods: The human breast cancer cell line MDA-MB-231 was used to evaluate effects of F. carica extracts. Effects of F. carica on cell viability were evaluated using MTT assays. Cell-cycle distribution was examined using cell-cycle analysis. Wound-healing assays were used to evaluate migration of MDA-MB-231. Quantitative reverse-transcription polymerase chain reaction was used to detect levels of Bax, p53, p21, GATA3, ELF5, cyclin-dependent kinases, MMP2, and tissue inhibitors of metalloproteinase. Results: We investigated the mechanism of anti-growth effects, and found that the expressions of genes that promote apoptosis were increased. In addition, the treated cells illustrated increased portion at S phase and changed expression of cyclin-dependent kinases, demonstrating cell-cycle arrest at the S phase. Furthermore, treated cells showed decreased cell mobility, which is essential for metastasis. Two of the active components of F. carica leaves, bergapten and psoralen, had similar anticancer effects as F. carica leaf extracts, indicating that these two components might play important roles in anticancer effects of F. carica leaves. Conclusion: Our findings suggest that F. carica leaves might be a good source to develop drugs for suppressing cancer-cell growth and migration to treat triple-negative breast cancers. Keywords: Ficus carica, breast cancer, MDA-MB-231, migration

Published
2018

37. The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation

Author

Jonathan D. Powell, Zizhen Kang, Katarzyna Bulek, Vincent K. Tuohy, Greg M. Delgoffe, Hui Xiao, Tae Whan Kim, Jeong Su Do, Booki Min, Muhammet F. Gulen, Mandy J. McGeachy, Kristian Sass Bak-Jensen, Cengiz Z. Altuntas, Yi Chen, Daniel J. Cua, Xiaoxia Li, and Wan Youzhong

Subjects
Encephalomyelitis, Autoimmune, Experimental, Cellular differentiation, Immunoblotting, Immunology, Enzyme-Linked Immunosorbent Assay, chemical and pharmacologic phenomena, Cell Separation, Protein Serine-Threonine Kinases, Interleukin-1 receptor, Biology, Transfection, Article, Mice, T-Lymphocyte Subsets, Animals, Immunoprecipitation, Immunology and Allergy, Cell Lineage, MOLIMMUNO, Receptor, PI3K/AKT/mTOR pathway, Cell Proliferation, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Cell growth, TOR Serine-Threonine Kinases, Interleukin-17, RPTOR, Intracellular Signaling Peptides and Proteins, Receptors, Interleukin-1, Cell Differentiation, hemic and immune systems, T-Lymphocytes, Helper-Inducer, Flow Cytometry, Molecular biology, Cell biology, Enzyme Activation, Infectious Diseases, CELLIMMUNO, Interleukin 17, Signal transduction, Signal Transduction
Abstract

SummaryInterleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG35-55) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.

Published
2010

38. From Human Genetic to Mouse Model: SF3B1 Mutation and its Impact on Chronic Lymphocytic Leukemia

Author

Wang, Lili, primary, Brooks, Angela, additional, Gambe, Rutendo, additional, Fan, Jean, additional, Sun, Jing, additional, Hergert, Sarah, additional, Wan, Youzhong, additional, Neuberg, Donna, additional, Kharchenko, Peter, additional, Meyerson, Matthew, additional, Fleming, Mark, additional, Ebert, Benjamin, additional, and Wu, Catherine, additional

Published
2016
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39. Comprehensive Bulk and Single Cell Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Author

Fan, Jean, primary, Wang, Lili, additional, Brooks, Angela N, additional, Wan, Youzhong, additional, Neuberg, Donna S, additional, Rassenti, Laura Z., additional, Ghia, Emanuela M., additional, Kipps, Thomas J., additional, Brown, Jennifer R., additional, Li, Shuqiang, additional, Livak, Kenneth J, additional, Meyerson, Matthew M., additional, Kharchenko, Peter V., additional, and Wu, Catherine J., additional

Published
2015
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40. Expressionof Sf3b1- K700Ein Murine B Cells Causes Pre-mRNA Splicing and Altered B Cell Differentiation and Function

Author

Wang, Lili, primary, Gambe, Rutendo, additional, Fan, Jean, additional, Wan, Youzhong, additional, Brooks, Angela N, additional, Sun, Jing, additional, Obeng, Esther A., additional, Neuberg, Donna S, additional, Meyerson, Matthew, additional, Fleming, Mark D., additional, Ebert, Benjamin L., additional, Carrasco, Ruben D., additional, and Wu, Catherine J, additional

Published
2015
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41. The dual functions of IRAK2 in TLR9–mediated interferon and proinflammatory cytokine production

Author

Wan, Youzhong, Kim, Tae Whan, Yamashita, Michifumi, Kang, Zizhen, Zhou, Hao, Yin, Weiguo, Thomas, James, Sen, Ganes C., Stark, George R., and Li, Xiaoxia

Subjects
Mice, Knockout, Rhadinovirus, Interferon Regulatory Factor-7, Down-Regulation, Interferon-alpha, hemic and immune systems, Dendritic Cells, Herpesviridae Infections, Interferon-beta, Ligands, Article, Recombinant Proteins, Mice, Tumor Virus Infections, Interleukin-1 Receptor-Associated Kinases, Toll-Like Receptor 9, Interferon Type I, Animals, Cytokines, CpG Islands, Inflammation Mediators, Cells, Cultured
Abstract

Bone marrow-derived plasmacytoid dendritic cells (pDCs) from IL-1R-associated kinase (IRAK)2-deficient mice produced more IFNs than did wild-type pDCs upon stimulation with the TLR9 ligand CpG. Furthermore, in CpG-stimulated IRAK2-deficient pDCs there was increased nuclear translocation of IFN regulatory factor 7, the key transcription factor for IFN gene transcription in these cells. In IRAK2-deficient macrophages, enhanced NF-κB activation and increased expression of CpG-induced genes were detected within 2 h after treatment. However, at later times, NF-κB activation was decreased and, in contrast to the results with IFN, there was less secretion of other proinflammatory cytokines (such as TNF-α) and chemokines in CpG-stimulated IRAK2-deficient pDCs and macrophages. Therefore, although IRAK2 is a negative regulator of TLR9-mediated IFN production through its modulation of the transcriptional activity of IFN regulatory factor 7, it is also a positive regulator of TLR9-mediated proinflammatory cytokine and chemokine production at some level subsequent to transcription.

Published
2011

42. SF3B1 and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia

Author

Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Wang, Lili, Lawrence, Michael S., Wan, Youzhong, Stojanov, Petar, Sougnez, Carrie, Stevenson, Kristen, Werner, Lillian, Sivachenko, Andrey, DeLuca, David S., Zhang, Li, Zhang, Wandi, Vartanov, Alexander R., Fernandes, Stacey M., Goldstein, Natalie R., Folco, Eric G., Cibulskis, Kristian, Tesar, Bethany, Sievers, Quinlan L., Shefler, Erica, Gabriel, Stacey B., Hacohen, Nir, Reed, Robin, Meyerson, Matthew L., Golub, Todd R., Neuberg, Donna S., Brown, Jennifer R., Getz, Gad, Wu, Catherine J., Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Wang, Lili, Lawrence, Michael S., Wan, Youzhong, Stojanov, Petar, Sougnez, Carrie, Stevenson, Kristen, Werner, Lillian, Sivachenko, Andrey, DeLuca, David S., Zhang, Li, Zhang, Wandi, Vartanov, Alexander R., Fernandes, Stacey M., Goldstein, Natalie R., Folco, Eric G., Cibulskis, Kristian, Tesar, Bethany, Sievers, Quinlan L., Shefler, Erica, Gabriel, Stacey B., Hacohen, Nir, Reed, Robin, Meyerson, Matthew L., Golub, Todd R., Neuberg, Donna S., Brown, Jennifer R., Getz, Gad, Wu, Catherine J., and Lander, Eric Steven

Abstract

Background: The somatic genetic basis of chronic lymphocytic leukemia, a common and clinically heterogeneous leukemia occurring in adults, remains poorly understood. Methods: We obtained DNA samples from leukemia cells in 91 patients with chronic lymphocytic leukemia and performed massively parallel sequencing of 88 whole exomes and whole genomes, together with sequencing of matched germline DNA, to characterize the spectrum of somatic mutations in this disease. Results: Nine genes that are mutated at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (with mutations occurring in 15% of patients). SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with chronic lymphocytic leukemia. We further discovered that tumor samples with mutations in SF3B1 had alterations in pre–messenger RNA (mRNA) splicing. Conclusions: Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia., National Institutes of Health (U.S.). National Human Genome Research Institute (Grant U54HG003067), National Cancer Institute (U.S.) (Grant 5R21CA115043-2)

Published
2014

43. Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Author

Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Landau, Dan A., Carter, Scott L., Stojanov, Petar, McKenna, Aaron, Stevenson, Kristen, Lawrence, Michael S., Sougnez, Carrie, Stewart, Chip, Sivachenko, Andrey, Wang, Lili, Wan, Youzhong, Zhang, Wandi, Shukla, Sachet A., Vartanov, Alexander, Fernandes, Stacey M., Saksena, Gordon, Cibulskis, Kristian, Tesar, Bethany, Gabriel, Stacey B., Hacohen, Nir, Meyerson, Matthew L., Neuberg, Donna S., Brown, Jennifer R., Getz, Gad, Wu, Catherine J., Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Landau, Dan A., Carter, Scott L., Stojanov, Petar, McKenna, Aaron, Stevenson, Kristen, Lawrence, Michael S., Sougnez, Carrie, Stewart, Chip, Sivachenko, Andrey, Wang, Lili, Wan, Youzhong, Zhang, Wandi, Shukla, Sachet A., Vartanov, Alexander, Fernandes, Stacey M., Saksena, Gordon, Cibulskis, Kristian, Tesar, Bethany, Gabriel, Stacey B., Hacohen, Nir, Meyerson, Matthew L., Neuberg, Donna S., Brown, Jennifer R., Getz, Gad, Wu, Catherine J., and Lander, Eric Steven

Abstract

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes., National Institute of General Medical Sciences (U.S.) (NHGRI-U54HG003067)

Published
2014

44. SF3B1 Mutation Alters The Selection Of 3' RNA Splice Sites In Chronic Lymphocytic Leukemia

Author

Wan, Youzhong, primary, Brooks, Angela N, additional, Wang, Lili, additional, Sougnez, Carrie, additional, Zhang, Wandi, additional, Wong, Jessica, additional, Landau, Dan-Avi, additional, Kotliar, Dylan, additional, Deluca, David, additional, Brown, Jennifer R., additional, Reed, Robin, additional, Getz, Gad, additional, Meyerson, Matthew, additional, and Wu, Catherine J, additional

Published
2013
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46. Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

Author

Landau, Dan A., primary, Carter, Scott L., additional, Stojanov, Petar, additional, McKenna, Aaron, additional, Stevenson, Kristen, additional, Lawrence, Michael S., additional, Sougnez, Carrie, additional, Stewart, Chip, additional, Sivachenko, Andrey, additional, Wang, Lili, additional, Wan, Youzhong, additional, Zhang, Wandi, additional, Shukla, Sachet A., additional, Vartanov, Alexander, additional, Fernandes, Stacey M., additional, Saksena, Gordon, additional, Cibulskis, Kristian, additional, Tesar, Bethany, additional, Gabriel, Stacey, additional, Hacohen, Nir, additional, Meyerson, Matthew, additional, Lander, Eric S., additional, Neuberg, Donna, additional, Brown, Jennifer R., additional, Getz, Gad, additional, and Wu, Catherine J., additional

Published
2013
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47. SF3B1and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia

Author

Wang, Lili, primary, Lawrence, Michael S., additional, Wan, Youzhong, additional, Stojanov, Petar, additional, Sougnez, Carrie, additional, Stevenson, Kristen, additional, Werner, Lillian, additional, Sivachenko, Andrey, additional, DeLuca, David S., additional, Zhang, Li, additional, Zhang, Wandi, additional, Vartanov, Alexander R., additional, Fernandes, Stacey M., additional, Goldstein, Natalie R., additional, Folco, Eric G., additional, Cibulskis, Kristian, additional, Tesar, Bethany, additional, Sievers, Quinlan L., additional, Shefler, Erica, additional, Gabriel, Stacey, additional, Hacohen, Nir, additional, Reed, Robin, additional, Meyerson, Matthew, additional, Golub, Todd R., additional, Lander, Eric S., additional, Neuberg, Donna, additional, Brown, Jennifer R., additional, Getz, Gad, additional, and Wu, Catherine J., additional

Published
2011
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48. Large-Scale CLL Genome Analysis Reveals Novel Cancer Genes, Including SF3B1

Author

Wan, Youzhong, primary, Lawrence, Michael S, additional, Wang, Lili, additional, Stojanov, Petar, additional, Sougnez, Carrie, additional, Stevenson, Kristen, additional, Werner, Lillian, additional, Zhang, Wandi, additional, Folco, Eric G, additional, Tesar, Bethany, additional, Sievers, Quinlan L, additional, Gabriel, Stacey, additional, Hacohen, Nir, additional, Reed, Robin, additional, Meyerson, Matthew, additional, Golub, Todd R., additional, Lander, Eric S, additional, Neuberg, Donna, additional, Brown, Jennifer R., additional, Getz, Gad, additional, and Wu, Catherine J, additional

Published
2011
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