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Radioresistance of B Cells in Chronic Lymphocytic Leukemia (CLL)

Dennis Otero

Appointment Period: 2003-2005 / Grant Year: [19,20]

Dennis OteroB cell Chronic Lymphocytic Leukemia (CLL) is the most frequent leukemia afflicting the Western world, yet no cure is available nor does there exist a successful standard therapy. Also, the normal cell population from which these leukemias originate has not been clearly identified. Unlike other more aggressive leukemias and lymphomas, CLL cells do not divide at a high rate and thus are not as amenable to radiation treatment. We are studying a B cell population in the mouse (B-1 cells) which shares many of the characteristics of CLL cells, including radioresistance. We have identified a biochemical pathway which may account for this resistance and we have proposed experiments to address this mechanism in mouse B cells and CLL cell lines. Mice were generated which are deficient for a gene involved in this biochemical pathway. B-1 cells from these mice are more sensitive to radioactivity, indicating the involvement of this pathway in radioresistance. A better understanding of the mechanisms involved in radioresistance of B-1 cells and CLL cells may lead to better therapies to treat these types of leukemia.

Otero DC, Rickert RC. CD19 function in early and late B cell development. II. CD19 facilitates the pro-B/pre-B transition. J Immunol. (2003) 171:5921-30. PMID: 14634103.

Otero DC, Anzelon AN, Rickert RC. CD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals. J Immunol. (2003) 170:73-83. PMID: 12496385.

Bonizzi G, Bebien M, Otero DC, Johnson-Vroom KE, Cao Y, Vu D, Jegga AG, Aronow BJ, Ghosh G, Rickert RC, Karin M. Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. EMBO J. (2004) 23:4202-10. PMID: 15470505; PMCID: PMC524385.

Del Nagro CJ, Otero DC, Anzelon AN, Omori SA, Kolla RV, Rickert RC. CD19 function in central and peripheral B-cell development. Immunol Res. (2005) 31:119-31. PMID: 15778510.

Enzler T, Bonizzi G, Silverman GJ, Otero DC, Widhopf GF, Anzelon-Mills A, Rickert RC, Karin M. Alternative and classical NF-kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease. Immunity. (2006) 25:403-15. PMID: 16973390.

Otero DC, Poli V, David M, Rickert RC. Cutting edge: inherent and acquired resistance to radiation-induced apoptosis in B cells: a pivotal role for STAT3. J Immunol. (2006) 177:6593-7. PMID: 17082570; PMCID: PMC2770730.

Pedersen IM, Otero D, Kao E, Miletic AV, Hother C, Ralfkiaer E, Rickert RC, Gronbaek K, David M. Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas. EMBO Mol Med. 2009 Aug;1(5):288-95. PubMed PMID:19890474; PubMed Central PMCID: PMC2771872.