The Peter Karches Center for Chronic Lymphocytic Leukemia
Director, Laboratory of Molecular Immunology (Gene Activation)
Assistant Professor, Department of Medicine,
The Feinstein Institute for Medical Research
Elmezzi Graduate School of Molecular Medicine
Phone: (516) 562-1207
Dr. Charles C. Chu received his doctor of philosophy degree in Genetics from the University of California, Berkeley, and was a postdoctoral fellow with William E. Paul, MD in the laboratory of Immunology at the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
In 1996, Dr. Chu became director of the laboratory of Molecular Immunology/Gene Activation at the Feinstein Institute for Medical Research. He is presently assistant professor of Medicine and of Molecular Medicine in the Hofstra North Shore-LIJ School of Medicine and assistant professor in the Elmezzi Graduate School of Molecular Medicine.
Dr. Chu’s research interests are currently focused on understanding the molecular basis for the development of B cell chronic lymphocytic leukemia (CLL). More broadly, Dr.Chu has interests in B cell biology, particularly B cell maturation and development and its relationship to disease and autoimmunity. Dr. Chu’s laboratory has found that the ability of the B cell antigen receptor (BCR) of CLL cells to bind antigen correlates with patient outcome. This key involvement of the B cell antigen receptor in CLL has been confirmed by several recent successful clinical trials blocking the BCR signaling pathway, which leads to CLL disease reduction. Dr. Chu’s laboratory is dedicated to research to finding better diagnostic tools and the ultimate cure for CLL patients.
CLL is a cancer, or uncontrolled expansion, of a cell in the immune system called a B lymphocyte. Normally, B cells produce antibodies to fight off infections that invade the body. Individual B cells generally do not live long and typically do not make up a large fraction of cells found in the blood. However, in CLL, a single B cell abnormally begins to grow uncontrollably, resulting in population of identical B cells derived from this original cell, or clonal expansion. This CLL clone grows and expands until it eventually makes up the majority of white blood cells found in the blood. Because CLL is clonal, all the leukemic cells make the same antibody molecule. The sequence of the CLL antibody molecule can be determined and characterized by the degree of mutation. Surprisingly, CLL patients with an unmutated (less than or equal to 2%) antibody sequence tend to have a worse clinical outcome. This dependence of clinical outcome on mutation suggests that an unidentified molecule that binds to the antibody may be important to the outcome of this disease. Furthermore, each B cell normally produces a single antibody molecule that is created via a DNA recombination and mutation process, resulting in a unique antibody that is extremely unlikely to be found in another person. However, in CLL, about 30% of patients share very similar antibody sequences! This is exceedingly improbable by random chance, and therefore suggests that a common molecule(s) binds the CLL antibodies of multiple CLL patients.
The goal of the proposed research is to improve the evaluation of chronic lymphocytic leukemia (CLL) patients with regard to the course of their disease. Both the level of IGHV mutation and the percentage of CD38+ cells in a CLL clone predict clinical outcome in ~75-80% patients. Dr. Chu’s team plans to improve the accuracy of prediction of CLL patient outcome by assessing hypervariable gene expression by CLL cells in combination with IGHV and CD38 measurements.
Dr. Chu’s role in this study comes about from the clinical and laboratory database that he has helped create and manage. Currently, his team has enrolled over 1500 patients in the CLL database; the database contains information on overall survival, time-to-first-treatment, IGHV mutation, and CD38 levels, as well as other clinical parameters. This database will provide the necessary IGHV, CD38, and clinical outcome measures needed to interpret their combined hypervariable gene expression analyses.
Dr. Chu’s broad background includes a focus in molecular genetics and in immunology, with specific training and expertise in key research areas for this application. As primary investigator or co-investigator on several private- and NIH-funded grants, he has experience not only with gene expression and statistical analyses, but also with administration of projects and collaboration with other researchers that have produced several peer-reviewed publications. The current application builds logically on his prior work, as his team has utilized CLL database analyses to show that CLL antibody binding to apoptotic cells correlates with IGHV mutation and clinical outcome (Blood 2010 115:3907).
University of Chicago, IL
Field of Study: Biology
University of California, Berkeley, CA
Field of Study: PhD
National Institutes of Health, Bethesda, MD
Field of Study: Immunology
- Chu, C.C., Catera, R., Hatzi, K., Yan, X.J., Zhang, L., Wang, X.B., Fales, H.M., Allen, S.L., Kolitz, J.E., Rai, K.R., and Chiorazzi, N. “Chronic lymphocytic leukemia antibodies with a common stereotypic rearrangement recognize non-muscle myosin heavy chain IIA.” Blood 2008; 112:5122-5129.
- Catera, R., Silverman, G.J., Hatzi, K., Seiler, T., Didier, S., Zhang, L., Hervé, M., Meffre, E., Oscier, D.G., Vlassara, H., Scofield, R.H., Chen, Y., Allen, S.L., Rai, K.R., Chu, C.C., and Chiorazzi, N.: “Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and chemical oxidation.” Mol. Med. 2008; 14:665-674.
- Seiler, T., Woelfle, M., Yancopoulos, S., Catera, R., Li, W., Hatzi, K., Moreno, C., Torres, M., Paul, S., Dohner, H., Stilgenbauer, S., Kaufman, M.S., Kolitz, J.E., Allen, S.L., Rai, K.R., Chu, C.C., Chiorazzi, N.: “Characterization of structurally-defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells.” Blood 2009; 114:3615-3624.
- Chu, C.C., Catera, R., Zhang, L., Didier, S., Agagnina, B.M., Damle, R.N., Kaufman, M.S., Kolitz, J.E., Allen, S.L., Rai, K.R., Chiorazzi, N.: “Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed non-muscle myosin heavy chain IIA: implications for patient outcome and cell of origin.” Blood 2010; 115:3907-3915.
- Ghiotto, F., Marcatili, P., Tenca, C., Calevo, M.G., Yan, X.-J., Albesiano, E., Bagnara, D., Colombo, M., Cutrona, G., Chu, C.C., Morabito, F., Bruno, S., Ferrarini, M., Tramontano, A., Fais, F., Chiorazzi, N.: “Mutation pattern of paired immunoglobulin heavy and light variable domains in chronic lymphocytic leukemia B-cells.” Mol. Med. 2011; 1188-1195.
- Chu, C.C., Zhang, L., Dhayalan, A., Agagnina, B.M., Magli, A.R., Fraher, G., Didier, S., Johnson, L.P., Kennedy, W.J., Damle, R.N., Yan, X.-J., Patten, P.E.M., Teichberg, S., Koduru, P., Kolitz, J.E., Allen, S.L., Rai, K.R., Chiorazzi, N.: “Torque teno virus 10 isolated by genome amplification techniques from a patient with concomitant chronic lymphocytic leukemia and polycythemia vera.” Mol. Med. 2011; 17:1338-1348.
- Hwang, K.K., Chen, X., Kozink, D.M., Gustilo, M., Marshall, D.J., Whitesides, J.F., Liao, H.X., Catera, R., Chu, C.C., Yan, X.-J., Luftig, M.A., Haynes, B.F., Chiorazzi, N.: “Enhanced outgrowth of EBV-transformed chronic lymphocytic leukemia B cells mediated by co-culture with macrophage feeder cells.” Blood 2012; 119:e35-e44.
- Agathangelidis, A., Darzentas, N., Hadzidimitriou, A., Brochet, X., Murray, F., Yan, X.-J., Davis, Z., van Gastel-Mol, E.J., Tresoldi, C., Chu, C.C., Cahill, N., Giudicelli, V., Tichy, B., Pedersen, L.B., Foroni, L., Bonello, L., Janus, A., Smedby, K., Anagnostopoulos, A., Merle-Beral, H., Laoutaris, N., Juliusson, G., di Celle, P.F., Pospisilova, S., Jurlander, J., Geisler, C., Tsaftaris, A., Lefranc, M.P., Langerak, A.W., Oscier, D.G., Chiorazzi, N., Belessi, C., Davi, F., Rosenquist, R., Ghia, P., Stamatopoulos, K.: “Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies.” Blood 2012; 119: 4467-4475.
- Patten, P.E.M., Chu, C.C., Albesiano, E., Damle, R.N., Yan, X.-J., Kim, D., Zhang, L., Magli, A.R., Barrientos, J., Kolitz, J.E., Allen, S.L., Rai, K.R., Roa, S., Mongini, P.K., MacCarthy, T., Scharff, M.D., Chiorazzi, N.: “IGHV unmutated and mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions.” Blood 2012; 120: 4802-4811.
- Cesano, A., Perbellini, O., Evensen, E., Chu, C.C., Cioffi, F., Ptacek, J., Damle, R.N., Chignola, R., Cordeiro, J., Yan, X.-J., Hawtin, R.E., Nichele, I., Ware, J.R., Cavallini, C., Lovato, O., Zanotti, R., Rai, K.R., Chiorazzi, N., Pizzolo, G., Scupoli, M.T.: “Association between B-cell receptor responsiveness and disease progression in B-cell chronic lymphocytic leukemia: results from single cell network profiling studies.” Haematologica 2012; In press.