Chronic lymphocyfic leukemia (CLL) is the most common type of adult leukemia whose clinical outcome is predicted in great part by the IgVn gene mutational status. Patients with IgVn un-mutated status (40% of all pafients at diagnosis) develop progressive disease at a median of 3 years and have inferior overall survival. In contrast, IgVn mutated pafients (60% of all CLL pafients at diagnosis) have a median progression time of 9.2 years, with some patients never requiring therapy. Reasons for adverse outcome in IgVn un-mutated disease include in part a high predisposifion to clonal evolufion. Idenfificafion of initiafion and progression events in IgVn un-mutated patients offers the potential to substantially improve risk stratification and also to idenfify novel targets crucial to initiation and progression for which new therapies can be developed. To identify novel initiating and progression events in CLL, our research groups together have employed two novel strategies. The first combines DNA methylation analysis with genetic studies of familial predisposition. This work demonstrated down-regulafion by DNA methylation of the pro-apoptotic gene DAPK1. This event not only is a general characteristic of human CLL but also is associated with familial predisposifion to developing CLL. We also have used the TCL1 transgenic mouse model of CLL that mimics IgVn un-mutated human CLL to identify addifional molecular events involved in CLL initiafion or progression. Molecular events identified in murine CLL were confirmed to also occur in human CLL. We now propose to expand our findings relative to these initiation and progression events through both a translational laboratory aim, focused on DAPK1 in CLL, and a clinical aim, focused on improving risk stratificafion in IgVn un-mutated CLL as part of a large North American Intergroup Phase III trial.
Our specific aims are to determine: 1) the importance of DAPK-mediated apoptosis in B-cells, frequency of allele-specific expression in CLL, and mechanisms by which DAPK1 gene expression is regulated in B- cells, with particular focus on regulators potentially relevant to B-cell transformation to CLL;and 2) the significance of baseline and serial molecular events in CLL inifiafion or progression on progression-free survival and clonal evolution in newly diagnosed CLL patients with IgVn un-mutated disease. Our overall hypothesis in this proposal is that improved understanding of inifiafing and progression events in CLL will lead to more effecfive risk stratified approaches for IgVn un-mutated CLL, and also novel targets for which therapies can be developed to potentially prevent clonal evolution or progression of this disease.

Public Health Relevance

This SPORE translational project performs detailed study of the CLL inifiating gene DAPK1 and assesses the impact of select molecular events on treatment free survival and clonal evolution in newly diagnosed IgVn un-mutated pafients. These findings may improve risk of progression of IgVn un-mutated CLL patients and also idenfify novel targets for targeted therapies to prevent clonal evolution or progression of this disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
United States
Zip Code
Walker, C J; Eisfeld, A-K; Genutis, L K et al. (2017) No evidence for microsatellite instability in acute myeloid leukemia. Leukemia 31:1474-1476
Sekeres, Mikkael A; Othus, Megan; List, Alan F et al. (2017) Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35:2745-2753
Eisfeld, Ann-Kathrin; Kohlschmidt, Jessica; Mrózek, Krzysztof et al. (2017) Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res 77:207-218
Park, I-K; Blum, W; Baker, S D et al. (2017) E3 ubiquitin ligase Cbl-b activates the p53 pathway by targeting Siva1, a negative regulator of ARF, in FLT3 inhibitor-resistant acute myeloid leukemia. Leukemia 31:502-505
Papaioannou, Dimitrios; Shen, Changxian; Nicolet, Deedra et al. (2017) Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia. Proc Natl Acad Sci U S A 114:E4641-E4647
Eisfeld, A-K; Kohlschmidt, J; Schwind, S et al. (2017) Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia. Leukemia 31:1278-1285
Papaioannou, Dimitrios; Nicolet, Deedra; Volinia, Stefano et al. (2017) Prognostic and biologic significance of long non-coding RNA profiling in younger adults with cytogenetically normal acute myeloid leukemia. Haematologica 102:1391-1400
Wiczer, Tracy E; Levine, Lauren B; Brumbaugh, Jessica et al. (2017) Cumulative incidence, risk factors, and management of atrial fibrillation in patients receiving ibrutinib. Blood Adv 1:1739-1748
Miller, Cecelia R; Ruppert, Amy S; Heerema, Nyla A et al. (2017) Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood Adv 1:1584-1588
Mani, R; Yan, R; Mo, X et al. (2017) Non-immunosuppressive FTY720-derivative OSU-2S mediates reactive oxygen species-mediated cytotoxicity in canine B-cell lymphoma. Vet Comp Oncol 15:1115-1118

Showing the most recent 10 out of 223 publications