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Previous Volume 351:893-901 August 26, 2004 Number 9 Next

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ABSTRACT

Background The course of chronic lymphocytic leukemia (CLL) is variable. In aggressive disease, the CLL cells usually express an unmutated immunoglobulin heavy-chain variable-region gene (IgV_H) and the 70-kD zeta-associated protein (ZAP-70), whereas in indolent disease, the CLL cells usually express mutated IgV_H but lack expression of ZAP-70.

Methods We evaluated the CLL B cells from 307 patients with CLL for ZAP-70 and mutations in the rearranged IgV_H gene. We then investigated the association between the results and the time from diagnosis to initial therapy.

Results We found that ZAP-70 was expressed above a defined threshold level in 117 of the 164 patients with an unmutated IgV_H gene (71 percent), but in only 24 of the 143 patients with a mutated IgV_H gene (17 percent, P<0.001). Among the patients with ZAP-70–positive CLL cells, the median time from diagnosis to initial therapy in those who had an unmutated IgV_H gene (2.8 years) was not significantly different from the median time in those who had a mutated IgV_H gene (4.2 years, P=0.07). However, the median time from diagnosis to initial treatment in each of these groups was significantly shorter than the time in patients with ZAP-70–negative CLL cells who had either mutated or unmutated IgV_H genes (P<0.001). The median time from diagnosis to initial therapy among patients who did not have ZAP-70 was 11.0 years in those with a mutated IgV_H gene and 7.1 years in those with an unmutated IgV_H gene (P<0.001).

Conclusions Although the presence of an unmutated IgV_H gene is strongly associated with the expression of ZAP-70, ZAP-70 is a stronger predictor of the need for treatment in B-cell CLL.

Source Information

From the Chronic Lymphocytic Leukemia Research Consortium (L.Z.R., L.H., T.L.T., L.C., M.J.K., J.G.G., D.S.N., I.W.F., K.R.R., J.C.B., N.E.K., A.G., T.J.K.); University of California, San Diego, La Jolla (L.Z.R., L.H., T.L.T., L.C., A.G., T.J.K.); M.D. Anderson Cancer Center, Houston (M.J.K.); Dana–Farber Cancer Institute, Boston (J.G.G., D.S.N.); Kimmel Cancer Center, Johns Hopkins, Baltimore (I.W.F.); Long Island Jewish Medical Center, New Hyde Park, N.Y. (K.R.R.); Ohio State University, Columbus (J.C.B.); Mayo Clinic, Rochester, Minn. (N.E.K.); and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco (A.W.).

Address reprint requests to Dr. Kipps at 9500 Gilman Dr., UCSD School of Medicine, La Jolla, CA 92093, or at tkipps{at}ucsd.edu.

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• Chiaretti, S., Guarini, A., De Propris, M. S., Tavolaro, S., Intoppa, S., Vitale, A., Iacobelli, S., Elia, L., Ariola, C., Ritz, J., Foa, R. (2006). ZAP-70 expression in acute lymphoblastic leukemia: association with the E2A/PBX1 rearrangement and the pre-B stage of differentiation and prognostic implications. Blood 107: 197-204 [Abstract] [Full Text]  
• Nabhan, C., Bitran, J. D. (2005). Chronic Lymphocytic Leukemia: To Transplant or Not to Transplant... That Is the Question?. JCO 23: 8126-8127 [Full Text]  
• Marasca, R., Maffei, R., Morselli, M., Zucchini, P., Castelli, I., Martinelli, S., Fontana, M., Ravanetti, S., Curotti, M., Leonardi, G., Cagossi, K., Partesotti, G., Torelli, G. (2005). Immunoglobulin Mutational Status Detected through Single-Round Amplification of Partial VH Region Represents a Good Prognostic Marker for Clinical Outcome in Chronic Lymphocytic Leukemia. J. Mol. Diagn. 7: 566-574 [Abstract] [Full Text]  
• Calin, G. A., Ferracin, M., Cimmino, A., Di Leva, G., Shimizu, M., Wojcik, S. E., Iorio, M. V., Visone, R., Sever, N. I., Fabbri, M., Iuliano, R., Palumbo, T., Pichiorri, F., Roldo, C., Garzon, R., Sevignani, C., Rassenti, L., Alder, H., Volinia, S., Liu, C.-g., Kipps, T. J., Negrini, M., Croce, C. M. (2005). A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic Leukemia. NEJM 353: 1793-1801 [Abstract] [Full Text]  
• Montserrat, E. (2005). Fighting CLL cells: deciphering the enemy. Blood 106: 2226-2226 [Full Text]  
• Castro, J. E., Prada, C. E., Loria, O., Kamal, A., Chen, L., Burrows, F. J., Kipps, T. J. (2005). ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia. Blood 106: 2506-2512 [Abstract] [Full Text]  
• Oppezzo, P., Vasconcelos, Y., Settegrana, C., Jeannel, D., Vuillier, F., Legarff-Tavernier, M., Kimura, E. Y., Bechet, S., Dumas, G., Brissard, M., Merle-Beral, H., Yamamoto, M., Dighiero, G., Davi, F., for the French Cooperative Group on CLL, (2005). The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia. Blood 106: 650-657 [Abstract] [Full Text]  
• Petlickovski, A., Laurenti, L., Li, X., Marietti, S., Chiusolo, P., Sica, S., Leone, G., Efremov, D. G. (2005). Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood 105: 4820-4827 [Abstract] [Full Text]  
• Raval, A., Lucas, D. M., Matkovic, J. J., Bennett, K. L., Liyanarachchi, S., Young, D. C., Rassenti, L., Kipps, T. J., Grever, M. R., Byrd, J. C., Plass, C. (2005). TWIST2 Demonstrates Differential Methylation in Immunoglobulin Variable Heavy Chain Mutated and Unmutated Chronic Lymphocytic Leukemia. JCO 23: 3877-3885 [Abstract] [Full Text]  
• Wiestner, A. (2005). More ZAP for chronic lymphocytic leukemia (CLL). Blood 105: 1839-1840 [Full Text]  
• Chen, L., Apgar, J., Huynh, L., Dicker, F., Giago-McGahan, T., Rassenti, L., Weiss, A., Kipps, T. J. (2005). ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 105: 2036-2041 [Abstract] [Full Text]  
• Chiorazzi, N., Rai, K. R., Ferrarini, M. (2005). Chronic Lymphocytic Leukemia. NEJM 352: 804-815 [Full Text]  
• Dighiero, G. (2005). CLL Biology and Prognosis. ASH Education Book 2005: 278-284 [Abstract] [Full Text]  
• Gascoyne, R. D. (2005). Hematopathology Approaches to Diagnosis and Prognosis of Indolent B-Cell Lymphomas. ASH Education Book 2005: 299-306 [Abstract] [Full Text]  
• Rassenti, L. Z., Neuberg, D. S., Keating, M. J., Gribben, J. G., Flinn, I. W., Rai, K. R., Byrd, J. C., Kay, N. E., Kipps, T. J. (2004). CD38 Compared with ZAP-70 or Immmunoglobulin Mutation Status as Predictor of Disease Progression in Chronic Lymphocytic Leukemia.. ASH ANNUAL MEETING ABSTRACTS 104: 2805-2805 [Abstract]