11 results on '"Xiao‐Jie Yan"'
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2. Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation
- Author
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Rosa Catera, Yun Liu, Chao Gao, Xiao-Jie Yan, Amanda Magli, Steven L. Allen, Jonathan E. Kolitz, Kanti R. Rai, Charles C. Chu, Ten Feizi, Kostas Stamatopoulos, and Nicholas Chiorazzi
- Subjects
Therapeutics. Pharmacology ,RM1-950 ,Biochemistry ,QD415-436 - Abstract
Abstract Amino acid replacement mutations in certain chronic lymphocytic leukemia (CLL) stereotyped B cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously, and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+ IGs, we found that IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bound naïve B cells. However, only subset 4 IGs reacted with memory B cells. Furthermore, subset 4 IGs did not bind DNA nor i or I carbohydrate antigens that are common targets of IGHV4-34-utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+ B cells in other diseases.
- Published
- 2017
- Full Text
- View/download PDF
3. Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation
- Author
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Xiao-Jie Yan, Chao Gao, Yun Liu, Rosa Catera, Nicholas Chiorazzi, Kanti R. Rai, Steven L. Allen, Kostas Stamatopoulos, Charles C. Chu, Ten Feizi, Amanda R. Magli, and Jonathan E. Kolitz
- Subjects
0301 basic medicine ,Chronic lymphocytic leukemia ,B-cell receptor ,Naive B cell ,Biology ,lcsh:Biochemistry ,03 medical and health sciences ,Negative selection ,Germline mutation ,Antigen ,hemic and lymphatic diseases ,Genetics ,medicine ,lcsh:QD415-436 ,Molecular Biology ,Genetics (clinical) ,lcsh:RM1-950 ,breakpoint cluster region ,medicine.disease ,Molecular biology ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Immunology ,biology.protein ,Molecular Medicine ,Antibody ,Research Article - Abstract
Amino acid replacement mutations in certain chronic lymphocytic leukemia (CLL) stereotyped B cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously, and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+ IGs, we found that IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bound naïve B cells. However, only subset 4 IGs reacted with memory B cells. Furthermore, subset 4 IGs did not bind DNA nor i or I carbohydrate antigens that are common targets of IGHV4-34-utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+ B cells in other diseases.
- Published
- 2017
4. A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo
- Author
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Jason D. Jacintho, Yalda Bravo, Lucia Correa, Xiao-Jie Yan, Davorka Messmer, Karin J. Stebbins, Geraldine Cabrera, Nicholas Simon Stock, Daniel S. Lorrain, Austin Chen, Nicholas Chiorazzi, Kymmy Lorrain, David Spaner, and Peppi Prasit
- Subjects
Transcriptional Activation ,Cell Survival ,Chronic lymphocytic leukemia ,Aminopyridines ,Peroxisome proliferator-activated receptor ,Apoptosis ,Biology ,Mice ,Downregulation and upregulation ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Genetics ,medicine ,Animals ,Humans ,PPAR alpha ,Receptor ,neoplasms ,Molecular Biology ,Genetics (clinical) ,Cell Proliferation ,chemistry.chemical_classification ,Sulfonamides ,Cell growth ,Fatty Acids ,Articles ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Cell biology ,Gene Expression Regulation, Neoplastic ,Leukemia ,chemistry ,Cell culture ,Molecular Medicine - Abstract
Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator–activated receptor (PPAR)-α, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPARα as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPARα, NXT629. NXT629 inhibited agonist-induced transcription of PPARα-regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative lymphoid compartment of CLL, we examined the activity of NXT629 on CLL cells that were stimulated to proliferate in vitro. NXT629 reduced the number of leukemia cells undergoing cell division. In addition, in two xenograft mouse models of CLL (one a model for nondividing and one for dividing CLL), NXT629 reduced the number of viable CLL cells in vivo. Overall, these results suggest that fatty acid metabolism promotes survival and proliferation of primary CLL cells and that inhibiting PPARα gene regulation could be a new therapeutic approach to treating CLL.
- Published
- 2015
5. Torque Teno Virus 10 Isolated by Genome Amplification Techniques from a Patient with Concomitant Chronic Lymphocytic Leukemia and Polycythemia Vera
- Author
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Lu Zhang, Sebastien Didier, Saul Teichberg, Arjun Dhayalan, William J. Kennedy, Jonathan E. Kolitz, Rajendra N. Damle, Charles C. Chu, Amanda R. Magli, Briana M. Agagnina, Prasad Koduru, Gia Fraher, Xiao-Jie Yan, Steven L. Allen, Piers E.M. Patten, Kanti R. Rai, Nicholas Chiorazzi, and Linda P. Johnson
- Subjects
Male ,Torque teno virus ,Chronic lymphocytic leukemia ,Blood Donors ,Genome, Viral ,Biology ,CD38 ,medicine.disease_cause ,Virus ,law.invention ,Polycythemia vera ,law ,hemic and lymphatic diseases ,Genetics ,medicine ,Humans ,Polycythemia Vera ,Molecular Biology ,Genetics (clinical) ,Polymerase chain reaction ,Aged ,Aged, 80 and over ,Mutation ,Reproducibility of Results ,Articles ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Virology ,DNA Virus Infections ,Case-Control Studies ,DNA, Viral ,Immunology ,Molecular Medicine ,Female ,IGHV@ ,Nucleic Acid Amplification Techniques - Abstract
An infectious etiology has been proposed for many human cancers, but rarely have specific agents been identified. One difficulty has been the need to propagate cancer cells in vitro to produce the infectious agent in detectable quantity. We hypothesized that genome amplification from small numbers of cells could be adapted to circumvent this difficulty. A patient with concomitant chronic lymphocytic leukemia (CLL) and polycythemia vera (PV) requiring therapeutic phlebotomy donated a large amount of phlebotomized blood to test this possibility. Using genome amplification methods, we identified a new isolate (BIS8-17) of torque teno virus (TTV) 10. The presence of blood isolate sequence 8-17 (BIS8-17) in the original plasma was confirmed by polymerase chain reaction (PCR), validating the approach, since TTV is a known plasma virus. Subsequent PCR testing of plasmas from additional patients showed that BIS8-17 had a similar incidence (~20%) in CLL (n = 48) or PV (n = 10) compared with healthy controls (n = 52). CLL cells do not harbor BIS8-17; PCR did not detect it in CLL peripheral blood genomic deoxyribonucleic acid (DNA) (n = 20). CLL patient clinical outcome or prognostic markers (immunoglobulin heavy chain variable region [IGHV ] mutation, CD38 or zeta-chain associated protein kinase 70 kDa [ZAP-70]) did not correlate with BIS8-17 infection. Although not causative to our knowledge, this is the first reported isolation and detection of TTV in either CLL or PV. TTV could serve as a covirus with another infectious agent or TTV variant with rearranged genetic components that contribute to disease pathogenesis. These results prove that this method identifies infectious agents and provides an experimental methodology to test correlation with disease.
- Published
- 2011
6. Erratum to: A Selective Novel Peroxisome Proliferator-Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo
- Author
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Davorka Messmer, Kymmy Lorrain, Karin Stebbins, Yalda Bravo, Nicholas Stock, Geraldine Cabrera, Lucia Correa, Austin Chen, Jason Jacintho, Nicholas Chiorazzi, Xiao Jie Yan, David Spaner, Peppi Prasit, and Daniel Lorrain
- Subjects
Genetics ,Molecular Medicine ,Molecular Biology ,Genetics (clinical) - Published
- 2015
7. Binding of CLL Subset 4 B Cell Receptor Immunoglobulins to Viable Human Memory B Lymphocytes Requires a Distinctive IGKV Somatic Mutation.
- Author
-
Catera, Rosa, Yun Liu, Chao Gao, Xiao-Jie Yan, Magli, Amanda, Allen, Steven L., Kolitz, Jonathan E., Rai, Kanti R., Chu, Charles C., Feizi, Ten, Stamatopoulos, Kostas, and Chiorazzi, Nicholas
- Subjects
- *
B cell receptors , *IMMUNOGLOBULINS , *LYMPHOCYTES , *GENETIC mutation , *CHRONIC lymphocytic leukemia - Abstract
Amino acid replacement mutations in certain chronic lymphocytic leukemia (CLL) stereotyped B cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously, and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+ IGs, we found that IGs from both subset 4 and non-subset 4 IGHV4- 34-expressing CLL cases bound naïve B cells. However, only subset 4 IGs reacted with memory B cells. Furthermore, subset 4 IGs did not bind DNA nor i or I carbohydrate antigens that are common targets of IGHV4-34-utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+ B cells in other diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
8. A Selective Novel Peroxisome Proliferator–Activated Receptor (PPAR)-α Antagonist Induces Apoptosis and Inhibits Proliferation of CLL Cells In Vitro and In Vivo.
- Author
-
Messmer, Davorka, Lorrain, Kymmy, Stebbins, Karin, Bravo, Yalda, Stock, Nicholas, Cabrera, Geraldine, Correa, Lucia, Chen, Austin, Jacintho, Jason, Chiorazzi, Nicholas, Xiao Jie Yan, and Spaner, David
- Abstract
Tumor-specific metabolic changes can reveal new therapeutic targets. Our findings implicate a supporting role for fatty acid metabolism in chronic lymphocytic leukemia (CLL) cell survival. Peroxisome proliferator–activated receptor (PPAR)-α, a major transcriptional regulator of fatty acid oxidation, was recently shown to be upregulated in CLL. To evaluate PPARα as a potential therapeutic target, we developed a highly selective, potent small molecule antagonist of PPARα, NXT629. NXT629 inhibited agonist-induced transcription of PPARα-regulated genes, demonstrating target engagement in CLL cells. Furthermore, NXT629 induced apoptosis of CLL cells even in the presence of a protective microenvironment. To mimic the proliferative lymphoid compartment of CLL, we examined the activity of NXT629 on CLL cells that were stimulated to proliferate in vitro. NXT629 reduced the number of leukemia cells undergoing cell division. In addition, in two xenograft mouse models of CLL (one a model for nondividing and one for dividing CLL), NXT629 reduced the number of viable CLL cells in vivo. Overall, these results suggest that fatty acid metabolism promotes survival and proliferation of primary CLL cells and that inhibiting PPARα gene regulation could be a new therapeutic approach to treating CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
9. Intraclonal Complexity in Chronic Lymphocytic Leukemia: Fractions Enriched in Recently Born/Divided and Older/Quiescent Cells.
- Author
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Calissano, Carlo, Damle, Rajendra N., Marsilio, Sonia, Xiao-Jie Yan, Yancopoulos, Sophia, Hayes, Gregory, Emson, Claire, Murphy, Elizabeth J., Hellerstein, Marc K., Sison, Cristina, Kaufman, Matthew S., Kolitz, Jonathan E., Allen, Steven L., Rai, Kanti R., Ivanovic, Ivana, Dozmorov, Igor M., Roa, Sergio, Scharff, Matthew D., Wentian Li, and Chiorazzi, Nicholas
- Subjects
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LEUKEMIA , *LYMPHOPROLIFERATIVE disorders , *CHRONIC lymphocytic leukemia , *LYMPHOBLASTIC leukemia , *LYMPHOCYTIC leukemia - Abstract
The failure of chemotherapeutic regimens to eradicate cancers often results from the outgrowth of minor subclones with more dangerous genomic abnormalities or with self-renewing capacity. To explore such intratumor complexities in B-cell chronic lymphocytic leukemia (CLL), we measured B-cell kinetics in vivo by quantifying deuterium (2H)-labeled cells as an indicator of a cell that had divided. Separating CLL clones on the basis of reciprocal densities of chemokine (C-X-C motif) receptor 4 (CXCR4) and cluster designation 5 (CD5) revealed that the CXCR4dimCD5bright (proliferative) fraction contained more 2H-labeled DNA and hence divided cells than the CXCR4brightCD5dim (resting) fraction. This enrichment was confirmed by the relative expression of two cell cycle-associated molecules in the same fractions, Ki-67 and minichromosome maintenance protein 6 (MCM6). Comparisons of global gene expression between the CXCR4dimCD5bright and CXCR4brightCD5dim fractions indicated higher levels of pro-proliferation and antiapoptotic genes and genes involved in oxidative injury in the proliferative fraction. An extended immunophenotype was also defined, providing a wider range of surface molecules characteristic of each fraction. These intraclonal analyses suggest a model of CLL cell biology in which the leukemic clone contains a spectrum of cells from the proliferative fraction, enriched in recently divided robust cells that are lymphoid tissue emigrants, to the resting fraction enriched in older, less vital cells that need to immigrate to lymphoid tissue or die. The model also suggests several targets preferentially expressed in the two populations amenable for therapeutic attack. Finally, the study lays the groundwork for future analyses that might provide a more robust understanding of the development and clonal evolution of this currently incurable disease. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
10. Mutation Pattern of Paired Immunoglobulin Heavy and Light Variable Domains in Chronic Lymphocytic Leukemia B Cells.
- Author
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Ghiotto, Fabio, Marcatili, Paolo, Tenca, Claudya, Calevo, Maria Grazia, Xiao-Jie Yan, Albesiano, Emilia, Bagnara, Davide, Colombo, Monica, Cutrona, Giovanna, Chu, Charles C., Morabito, Fortunato, Bruno, Silvia, Ferrarini, Manlio, Tramontano, Anna, Fais, Franco, and Chiorazzi, Nicholas
- Subjects
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GENETIC mutation , *LYMPHOCYTIC leukemia , *ANTIGEN presenting cells , *LYMPHOPROLIFERATIVE disorders , *CHRONIC lymphocytic leukemia - Abstract
B-cell chronic lymphocytic leukemia (CLL) patients display leukemic clones bearing either germline or somatically mutated immunoglobulin heavy variable (IGHV ) genes. Most information on CLL immunoglobulins (Igs), such as the definition of stereotyped B-cell receptors (BCRs), was derived from germline unmutated Igs. In particular, detailed studies on the distribution and nature of mutations in paired heavy- and light-chain domains of CLL clones bearing mutated Igs are lacking. To address the somatic hypermutation dynamics of CLL Igs, we analyzed the mutation pattern of paired IGHV-diversity-joining (IGHV-D-J ) and immunoglobulin kappa/lambda variable-joining (IGK/LV-J ) rearrangements of 193 leukemic clones that displayed ⩾2% mutations in at least one of the two immunoglobulin variable (IGV ) genes (IGHV and/or IGK/LV ). The relationship between the mutation frequency in IGHV and IGK/LV complementarity determining regions (CDRs) and framework regions (FRs) was evaluated by correlation analysis. Replacement (R) mutation frequency within IGK/LV chain CDRs correlated significantly with mutation frequency of paired IGHV CDRs in λ but not κ isotype CLL clones. CDRs of IGKV-J rearrangements displayed a lower percentage of R mutations than IGHVs. The frequency/ pattern of mutations in kappa CLL Igs differed also from that in κ-expressing normal B cells described in the literature. Instead, the mutation frequency within the FRs of IGHV and either IGKV or IGLV was correlated. Notably, the amount of diversity introduced by replaced amino acids was comparable between IGHVs and IGKVs. The data indicate a different mutation pattern between κ and λ isotype CLL clones and suggest an antigenic selection that, in κ samples, operates against CDR variation. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
11. Surface Expression of Bcl-2 in Chronic Lymphocytic Leukemia and Other B-Cell Leukemias and Lymphomas Without a Breakpoint t(14;18).
- Author
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McCarthy, Brian A., Boyle, Erin, Xue Ping Wang, Guzowski, Dorothy, Paul, Santanu, Catera, Rosa, Trott, Joshua, Xiao-jie Yan, Croce, Carlo M., Damle, Rajendra, Yancopoulos, Sophia, Messmer, Bradley T., Lesser, Martin, Allen, Steven L., Rai, Kanti R., and Chiorazzi, Nicholas
- Subjects
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GENE expression , *GENETIC regulation , *B cell lymphoma , *ANTIGEN presenting cells , *LYMPHOCYTES , *LYMPHOMAS - Abstract
Since its discovery in follicular lymphoma cells at the breakpoint t(14;18), Bcl-2 has been studied extensively in many basic and clinical science settings. Bcl-2 can locate as an integral mitochondrial membrane component,where its primary role is to block apoptosis by maintaining membrane integrity. Here we show that Bcl-2 also can position on the outer cell surface membrane of B cells from patients with chronic lymphocytic leukemia (B-CLL) and certain other leukemias that do not classically possess the chromosomal breakpoint t(14;18).Although low levels of Bcl-2 can be detected on the surface membrane of apparently healthy leukemic and normal B cells, expression of Bcl-2 correlates best with spontaneous or induced apoptosis. Notably, upon induction of apoptosis, B-CLL cells were much more efficient in upregulating surface Bcl-2 than normal B cells. It is not clear if this surface membrane expression is a passive consequence of the apoptotic process or an active attempt by the B cell to abort cell death by stabilizing the plasma membrane. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
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