From the Shipp Laboratory: An Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B-Cell Lymphoma
Our translational research group focuses on the pathogenesis and treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). DLBCL, the most common non-Hodgkin lymphoma in adults, is a clinically and genetically heterogeneous disorder. With current immuno-chemotherapy, over 60 percent of patients with DLBCL can be cured; however, the remaining patients succumb to their disease.
Despite recent advances in the molecular understanding of DLBCL pathogenesis, clinical risk models such as the International Prognostic Index (IPI) are still widely used to identify patients who are unlikely to be cured with current therapy. Although the IPI is robust and reproducible, the link between the included clinical parameters and underlying biology or targeted treatment remains to be defined. We performed this study to better define the molecular characteristics of DLBCL associated with poor outcomes.
DLBCLs originate from germinal center (GC) B-cells, which have high growth rates and genomic instability. As a consequence, DLBCLs exhibit multiple low-frequency genetic mutations, including copy number alterations (CNAs). Using a combination of high-density single nucleotide polymorphism (HD-SNP) array-based copy number assessments, gene expression profiling, and pathway analyses, we have comprehensively defined recurrent CNAs, associated candidate driver genes, and perturbed signaling pathways in a large series of newly diagnosed DLBCLs (Monti and Chapuy et al, Cancer Cell 2012; 22:359-372).
This approach revealed a large complementary set of CNAs that decreased p53 activity and perturbed cell cycle regulation. Patients could be divided into two groups: those with numerous CNAs in p53 and cell cycle genes ("Complex"), and those without such alterations ("Clean"). The "Complex" CNA-associated signature of p53 deficiency and cell cycle deregulation was highly predictive for inferior outcome in DLBCL patients who were treated with R-CHOP.
The prognostic value of the perturbed p53 signaling/cell cycle deregulation signature, as well as its association with increased activation of cyclin-dependent kinases (CDK4/6, CDK2, and CDK1), prompted us to evaluate the activity of a broad-acting CDK inhibitor in DLBCL. Following treatment, DLBCL cell lines with the signature of p53 deficiency and cell cycle deregulation exhibited decreased proliferation and CDK activity, and increased apoptosis in vitro and significantly reduced tumor growth in vivo. Therefore, prognostically significant, genetically driven cell cycle deregulation in DLBCL may be amenable to targeted treatment.
In the future, we will prospectively analyze copy number alterations in DLBCL patients treated at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). This additional molecular information will allow us to accomplish two goals: to enhance our ability to determine prognosis, and to predict response to novel therapies.
— Margaret A. Shipp, MD, Chief of the DF/BWCC Division of Hematologic Neoplasia and Director of the DF/BWCC Adult Lymphoma Program, with Andrew Lane, MD, PhD, Oncologist in the DF/BWCC Adult Bone Marrow/Stem Cell Transplantation Program