Charles C. Chu, Ph.D.

Associate Investigator, Center for Experimental Immunology
Director, Laboratory of Molecular Immunology (Gene Activation) Assistant Professor, New York University School of Medicine

The Feinstein Institute for Medical Research
350 Community Drive
Manhasset, NY   11030
Telephone:  (516) 562-1207
Fax:   (516) 562-1322
Email:   cchu@nshs.edu

Education: B.A.  1981  Biology, University of Chicago
Ph.D.  1988  Genetics, University of California, Berkeley

The current interest of our laboratory is focused on understanding the molecular basis for the development of B cell chronic lymphocytic leukemia (B-CLL). B-CLL is the most common Western adult leukemia with an estimated 15,110 new cases and 4,390 deaths for the year 2008 in the United States of America alone. Presently, the cure and cause of B-CLL is not clearly known.

B-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 B-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 B-CLL clone grows and expands until it eventually makes up the majority of white blood cells found in the blood. Because B-CLL is clonal, all the leukemic cells make the same antibody molecule. The sequence of the B-CLL antibody molecule can be determined and characterized by the degree of mutation. Surprisingly, B-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, at least 27% of B-CLL patients share very similar antibody sequences, suggesting that there is some common molecule that binds the antibodies of multiple B-CLL patients.

Currently, the major project of our laboratory is defining the molecule(s) that bind to the antibodies made by B-CLL cells. B-CLL patients can be grouped into subsets based on the similarity of their antibody sequences. We have focused on one subset of B-CLL patients that express an unmutated antibody characterized by a heavy (H) chain encoded by IGHV1-69, IGHD3-16, and IGHJ3 and a light (L) chain generally encoded by IGKV3-20. Antibodies from this stereotypic subset (called subset 6) bind a characteristic cytoplasmic protein in human cells. We have recently shown that this protein is non-muscle myosin heavy chain IIA (MYHIIA) (see reference 26). At present, we are studying the mechanism that allows MYHIIA to become exposed on the outside of the cell and thus be available for stimulating B-CLL cell growth from this subset of patients. Because MYHIIA is a very large molecule, we are engaged in fragmenting this protein to determine the portion of MYHIIA that is responsible for binding to this B-CLL subset of antibodies. In addition, we are actively pursuing the molecules bound by other subsets of B-CLL patients with different antibody sequences. We anticipate that we may find common features of the molecules bound by B-CLL antibodies that will help us understand the growth and development of this leukemia. Finally, the identification of the molecules that bind to B-CLL antibodies will allow us to design therapeutic molecules that interfere with this binding and therefore may help cure this disease.

Our laboratory is pursuing a second project that may have relevance to the molecular mechanism autoimmune diseases, such as systemic lupus erythematosus (SLE), an autoimmune disorder that afflicts between 500,000 and 1,000,000 people in the United States.

In SLE, antibodies are produced against the body’s own tissues, eliciting immune responses. This aberrant activity is the result of B cell dysregulation. Our studies have focused on Interleukin-Four Induced Gene-1 (Fig1 or IL4I1) for a number of reasons. First, IL4I1 is induced by interleukin-4, a key immunoregulatory cytokine. Second, IL4I1 RNA expression is primarily limited to B cells and antigen-presenting cells found in immune tissues, such as the spleen, lymph node, and bone marrow. Interestingly, the mouse IL4I1 gene maps to a small genetic interval that contains the Lbw5 and Sle3 SLE susceptibility loci. Thus, it is possible that defects in Il4i1 result in susceptibility to SLE.

PUBLICATIONS:

Clark, A.J., Sandler, S.J., Willis, D.K., Chu, C.C., Blanar, M.A., and Lovett, S.T.:  Genes of the RecE and RecF pathways of conjugational recombination in Escherichia coli.  Cold Spring Harbor Symp. Quant. Biol. 1984; 49:453-462.

Chu, C.C., and Clark, A.J.:  A 10- rather than 9-bp duplication associated with insertion of Tn5 in Escherichia coli K-12.  Plasmid 1989; 22:260-264.

Chu, C.C., Templin, A., and Clark, A.J.:  Suppression of a frameshift mutation in the recE gene of Escherichia coli K-12 occurs by gene fusion.  J. Bacteriol. 1989; 171:2101 -2109.

Mahajan, S.K., Chu, C.C., Willis, D.K., Templin, A., and Clark, A.J.:  Physical analysis of spontaneous and mutagen-induced mutants of Escherichia coli K-12 expressing DNA exonuclease VIII activity.  Genetics 1990; 125:261-273.

Scappino, L.A., Chu, C., and Gritzmacher, C.A.:  Extended nucleotide sequence of the switch region of the murine gene encoding immunoglobulin E. Gene 1991; 99:295-296.

Tanaka, T., Chu, C.C., and Paul, W.E.:  An antisense oligonucleotide complementary to a sequence in I2b increases 2b germline transcripts, stimulates B cell DNA synthesis, and inhibits immunoglobulin secretion.  J. Exp. Med. 1992; 175:597-607.

Chu, C.C., Paul, W.E., and Max, E.E.:  Quantitation of immunoglobulin -1 heavy chain switch region recombination by a digestion-circularization polymerase chain reaction method.  Proc. Natl. Acad. Sci. USA. 1992; 89:6978-6982.

Chu, C.C., Max, E.E., and Paul, W.E.:  DNA rearrangement can account for in vitro switching to IgG1.  J. Exp. Med.; 1993; 178:1381-1390.

Mandler, R., Chu, C.C., Paul, W.E., Max, E.E., and Snapper, C.M.:  Interleukin-5 induces S-S1 DNA rearrangement in B cells activated with dextran-anti-IgD antibodies and interleukin-4:  A three component model for Ig class switching.  J. Exp. Med., 1993; 178:1577-1586.

Clark, A.J., Sharma, V., Brenowitz, S., Chu, C.C., Sandler, S., Satin, L., Templin, A., Berger, I., and Cohen, A.:  Genetic and molecular analysis of the C-terminal region of the recE gene from the Rac prophage of Escherichia coli K-12 reveal the recT gene.  J. Bacteriol. 1993; 175:7673-7682.

Clark, A.J., Satin, L., and Chu, C.C.:  Transcription of the E. coli recE gene from a promoter in Tn5 and IS50.  J. Bacteriol. 1994; 176:7024-7031.

Nakanishi, K., Yoshimoto, T., Chu, C.C., Matsumoto, H., Hase, K., Nagai, N., Tanaka, T., Miyasaka, M., Paul, W.E., and Shinka, S.:  IL-2 inhibits IL-4 dependent IgE and IgG1 production in vitro and in vivo.  Int. Immunol. 1995; 7:259-268.

Shimoda, K., van Deursent, J., Sangster, M.Y., Sarawar, S.R., Carson, R.T., Tripp, R.A., Chu, C., Quelle, F.W., Nosaka, T., Vignali, D.A.A., Doherty, P.C., Grosveld, G., Paul, W.E. and Ihle, J.N.:  Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene.  Nature 1996; 380:630-633.

Chu, C.C., and Paul, W.E.: Fig1, an Interleukin-4-induced Mouse B Cell Gene Isolated by cDNA Representational Difference Analysis.  Proc. Natl. Acad. Sci., USA. 1997; 94:2507-2512.

Chu, C.C. and Paul, W.E.:  Expressed Genes in Interleukin-4 Treated B Cells Identified by cDNA Representational Difference Analysis.  Mol. Immunol. 1998; 35:487-502.

Hirose, N., Williams, R., Alberts, A. R., Furie, R. A., Chartash, E. K., Jain, R. I., Sison, C., Lahita, R. G., Merrill, J. T., Cucurull, E., Gharavi, A. E., Sammaritano, L. R., Salmon, J. E., Hashimoto, S., Sawada, T., Chu, C. C., Gregersen, P. K. and Chiorazzi, N.:  A role for polymorphism at position 247 in the beta2-glycoprotein I gene in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid syndrome.  Arthritis Rheum. 1999; 42:1655-61.

Chavan, S. S., Tian, W., Hsueh, K., Jawaheer, D., Gregersen, P. K., and Chu, C. C.:  Characterization of the human homolog of the IL-4 induced  gene-1 (Fig1). Biochim. Biophys. Acta 2002; 1576:70-80.

Tian, W., Chua, K., Strober, W., and Chu, C.C.:  ILG1: A new integrase-like gene that is a marker of bacterial contamination by the laboratory Escherichia coli strain TOP10F’. Mol. Med. 2002; 8:405-416.

Miura, Y., Chu C. C., Dines, D. M., Asnis, S. E., Furie, R. A., and Chiorazzi, N.:  Diversification of the Ig variable region gene repertoire of synovial B-lymphocytes by nucleotide insertion and deletion. Mol. Med. 2003; 9:166-174.

Chavan, S. S., Mason, J. M., Porti, D., Barcia, M., and Chu, C. C.:  Interleukin-4 induced gene-1 (IL4I1) may affect antigen presenting cell function. In Immunology 2004, Monduzzi Editore, Montreal, Quebec, Canada, vol. 1., p. 59-64, 2004.

Mason J. M., Naidu M. D., Barcia M., Porti D., Chavan, S. S., and Chu C. C.:  Interleukin-four induced gene-1 (Il4i1) is a leukocyte L-amino acid oxidase with an unusual acidic pH preference and lysosomal localization. J. Immunol. 2004; 173:4561-4567.

Desai, A., Victor-Vega, C., Gadangi, S., Montesinos, M. C., Chu, C. C., and Cronstein, B. N.:  Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol. Pharmacol. 2005; 67:1406-1413.

Guzowski, D., Chandrasekaran, A., Gawel, C., Palma, J., Koenig, J., Wang, X. P., Dosik, M., Kaplan, M., Chu, C. C., Chavan, S. S., Furie, R., Albesiano, E., Chiorazzi, N., and Goodwin, L.:  Analysis of single nucleotide polymorphisms in the promoter region of interleukin-10 by denaturing high-performance liquid chromatography. J. Biomol. Tech. 2005; 16:154-166.

Benoff, S., Chu, C. C., Marmar, J. L., Sokol, R. Z., Goodwin, L. O., and Hurley,I. R.: Voltage-dependent calcium channels in mammalian spermatozoa revisited. Front. Biosci. 2007; 12:1420-1449.

Chu, C.C., Zhang, L., Teichberg, S., Allen, S.L., Rai, K.R., and Chiorazzi, N.: Plasma from a B-cell chronic lymphocytic patient with polycythemia vera contains viral and bacterial DNA. In 13th International Congress of Immunology, Monduzzi Editore, Rio de Janeiro, Brazil, p. 589-595. 2007.

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.