This core will provide a seamless translational infrastructure to support the research on CLL tissues planned in this application. This will include the provision of fresh or frozen primary CLL samples (peripheral blood, bone marrow and lymph node) for all in vitro experiments, with full clinical annotation and follow-up, from among the over 1200 patients already enrolled in the DFCI CLL tissue bank as well as newly enrolled patients. The core includes extensive serial sampling from many CLL patients treated with novel agents, and will focus particularly on the acquisition of progression and relapsed samples during this grant period. This core also includes an effort to develop the capability of using primary CLL cells to generate in vivo primagraft models. These models are a significant and increasingly appreciated tool for the analysis of newly identified genetic lesions, associated signaling and survival pathways, rational therapeutic targets and mechanisms of drug resistance. CLL cells or isogenic cell lines will be delivered by tail vein injection or directly implanted within the coated scaffolds. CLL cells delivered to the scaffolds are expected to engraft within this ?humanized mouse? system which is meant to simulate vital human-human heterotypic interactions between CLL and BM cells. These primagraft models could then be used to characterize biology and assess response to therapy of the CLLs. This core ultimately also readily provides the opportunity for translation to clinical research trials in humans, as our clinical DFCI CLL program consists of recognized leaders in managing all phases of clinical research trials as well as multicenter studies.

Public Health Relevance

The mission of Core B is to characterize and bank tumor samples from CLL patients representing a full range of biologic characteristics and receiving a full range of therapies. This tissue resource will enable the fundamental discoveries required to understand the pathogenesis of the disease and move toward improved therapies and eventual cure. As part of this effort, core B will work to develop mouse models of human CLLs, which would serve as an extraordinary resource for this study of CLL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA206978-01
Application #
9149998
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (M1))
Project Start
Project End
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$250,834
Indirect Cost
$83,838
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Ten Hacken, Elisa; Valentin, Rebecca; Regis, Fara Faye D et al. (2018) Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight 3:
Lampson, Benjamin L; Brown, Jennifer R (2018) Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? Expert Rev Hematol 11:185-194
Wang, Lili; Livak, Kenneth J; Wu, Catherine J (2018) High-dimension single-cell analysis applied to cancer. Mol Aspects Med 59:70-84
Landau, Dan A; Sun, Clare; Rosebrock, Daniel et al. (2017) The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun 8:2185
Compagno, Mara; Wang, Qi; Pighi, Chiara et al. (2017) Phosphatidylinositol 3-kinase ? blockade increases genomic instability in B cells. Nature 542:489-493
Ten Hacken, Elisa; Gui├Ęze, Romain; Wu, Catherine J (2017) SnapShot: Chronic Lymphocytic Leukemia. Cancer Cell 32:716-716.e1
Murphy, E J; Neuberg, D S; Rassenti, L Z et al. (2017) Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia. Leukemia 31:1348-1354
Deng, J; Isik, E; Fernandes, S M et al. (2017) Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 31:2075-2084
Tiao, G; Improgo, M R; Kasar, S et al. (2017) Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia 31:2244-2247
Wang, Lili; Fan, Jean; Francis, Joshua M et al. (2017) Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia. Genome Res 27:1300-1311

Showing the most recent 10 out of 11 publications