B-cell chronic lymphocytic leukemia (B-CLL) is a common leukemia with significant patient variability to therapy and without a definitive curative approach. However, B-CLL likely represents distinct disease subtypes defined by a variety of cellular and molecular features including apoptosis resistance, chromosomal abnormalities, and status of immunoglobulin (Ig) genes in the CLL B cell clones. Specifically, there are recent findings that a strong relationship exists between clinical outcome and the presence or absence of somatic mutations in the Ig heavy chain variable region genes in the B-CLL clone. The exact biologic features that determine why the two B-CLL patient subgroups fare so differently are unknown. More importantly, no correlation to date has been made between Ig mutation status and specific therapeutic strategies, response rates, and key biologic and molecular features such as apoptosis, drug sensitivities, and chromosomal abnormalities. In this proposal, therefore, we will characterize apoptosis, cytogenetic abnormalities, and gene expression profiles of germline versus somatic mutation type B-CLL clones and more importantly, we will directly correlate these molecular parameters with clinical outcome to therapy. Our specific hypothesis is that one or more of these key discriminating features of B-CLL clones will allow us to predict disease progression and therapeutic response in CLL subsets. To test this hypothesis, we will conduct laboratory studies in two North Central Cancer Treatment Group clinical trials for B-CLL: one trial designed to test the efficacy of Fludarabine given on an alternating basis with cyclophosphamide to previously untreated CLL patients; and the other which uses Gemcitabine for previously treated CLL patients. Specifically, we propose to 1) determine the relationship between B-CLL Ig VH gene region status and key biological, genetic, and molecular features exhibited by the leukemic clone; and 2) examine the association between clinical response parameters for patients treated with fludarabine and cyclophosphamide or Gemcitabine and clonal biologic and molecular features.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA091542-02
Application #
6515116
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Wu, Roy S
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2005-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$317,475
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Fink, Stephanie R; Paternoster, Sarah F; Smoley, Stephanie A et al. (2005) Fluorescent-labeled DNA probes applied to novel biological aspects of B-cell chronic lymphocytic leukemia. Leuk Res 29:253-62
Kay, Neil E; Bone, Nancy D; Lee, Yean K et al. (2005) A recombinant IL-4-Pseudomonas exotoxin inhibits protein synthesis and overcomes apoptosis resistance in human CLL B cells. Leuk Res 29:1009-18
Shanafelt, Tait D; Lee, Yean K; Bone, Nancy D et al. (2005) Adaphostin-induced apoptosis in CLL B cells is associated with induction of oxidative stress and exhibits synergy with fludarabine. Blood 105:2099-106
Ghobrial, Irene M; Bone, Nancy D; Stenson, Mary J et al. (2004) Expression of the chemokine receptors CXCR4 and CCR7 and disease progression in B-cell chronic lymphocytic leukemia/ small lymphocytic lymphoma. Mayo Clin Proc 79:318-25
Dewald, Gordon W; Brockman, Stephanie R; Paternoster, Sarah F et al. (2003) Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia. Br J Haematol 121:287-95
Chandra, Joya; Hackbarth, Jennifer; Le, Son et al. (2003) Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells. Blood 102:4512-9
Jelinek, Diane F; Tschumper, Renee C; Stolovitzky, Gustavo A et al. (2003) Identification of a global gene expression signature of B-chronic lymphocytic leukemia. Mol Cancer Res 1:346-61
Kay, Neil E; Hamblin, Terry J; Jelinek, Diane F et al. (2002) Chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program :193-213