Project description:B cell chronic lymphocytic leukemia - A model with immune response
Seema Nanda 1, , Lisette dePillis 2, and Ami Radunskaya 3,
1.
Tata Institute of Fundamental Research, Centre for Applicable Mathematics, Bangalore 560065, India
2.
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
3.
Department of Mathematics, Pomona College, Claremont, CA, 91711, United States
Abstract
B cell chronic lymphocytic leukemia (B-CLL) is known to have substantial clinical heterogeneity. There is no cure, but treatments allow for disease management. However, the wide range of clinical courses experienced by B-CLL patients makes prognosis and hence treatment a significant challenge. In an attempt to study disease progression across different patients via a unified yet flexible approach, we present a mathematical model of B-CLL with immune response, that can capture both rapid and slow disease progression. This model includes four different cell populations in the peripheral blood of humans: B-CLL cells, NK cells, cytotoxic T cells and helper T cells. We analyze existing data in the medical literature, determine ranges of values for parameters of the model, and compare our model outcomes to clinical patient data. The goal of this work is to provide a tool that may shed light on factors affecting the course of disease progression in patients. This modeling tool can serve as a foundation upon which future treatments can be based.
Keywords: NK cell, chronic lymphocytic leukemia, mathematical model, T cell., B-CLL.
Project description:This work shows that signaling-lymphocytic-activation-molecule-1 (SLAMF1), a co-stimulatory molecule and a microbial sensor, is expressed by normal CD19+/CD5+ B-lymphocytes. Its expression is lost in a subset of patients with chronic lymphocytic leukemia (CLL) characterized by an aggressive form of the disease, with shorter time to first treatment and overall survival. Silencing of SLAMF1 in the CLL-like Mec-1 cell line (constitutively SLAMF1+) modulated pathways connected to cell migration, cytoskeletal organization and intracellular vesicle formation/recirculation. Loss of SLAMF1 was associated to increased expression of CXCR4, CD38 and CD44, positively affecting chemotactic responses to CXCL12. Ligation of SLAMF1 with an agonistic monoclonal antibody promoted the autophagic flux, by increasing reactive oxygen species (ROS) accumulation and inducing phosphorylation of p38, JNK1/2 and bcl-2. The direct consequence was the assembly of the autophagy macro-complex that included SLAMF1, the scaffold protein Beclin1 and the enzyme Vps34. Consistently, SLAMF1-silenced cells or SLAMF1low primary CLL cells were resistant to autophagy-activating therapeutic agents, such as fludarabine or the BH3 mimetic ABT-737. These results indicate that loss of SLAMF1 expression modulates genetic pathways regulating chemotaxis and autophagy and potentially affecting drug responses, thus providing a likely explanation for the unfavorable clinical outcome experienced by this patient subset. Microarrays were performed comparing genetic signature of CLL-like Mec-1 cell line (constitutively SLAMF1+), transfected with a non-effective (scrambled) shRNA cassette (TR30013) used as control, and a Mec-1 variant generated silencing SLAMF1 gene using pGFP-V-RS construct for SLAMF1 shRNA (TG309422). For each cell line variants, grown in vitro in complete medium, three biological replicates were included in the chip.
Project description:This work shows that signaling-lymphocytic-activation-molecule-1 (SLAMF1), a co-stimulatory molecule and a microbial sensor, is expressed by normal CD19+/CD5+ B-lymphocytes. Its expression is lost in a subset of patients with chronic lymphocytic leukemia (CLL) characterized by an aggressive form of the disease, with shorter time to first treatment and overall survival. Silencing of SLAMF1 in the CLL-like Mec-1 cell line (constitutively SLAMF1+) modulated pathways connected to cell migration, cytoskeletal organization and intracellular vesicle formation/recirculation. Loss of SLAMF1 was associated to increased expression of CXCR4, CD38 and CD44, positively affecting chemotactic responses to CXCL12. Ligation of SLAMF1 with an agonistic monoclonal antibody promoted the autophagic flux, by increasing reactive oxygen species (ROS) accumulation and inducing phosphorylation of p38, JNK1/2 and bcl-2. The direct consequence was the assembly of the autophagy macro-complex that included SLAMF1, the scaffold protein Beclin1 and the enzyme Vps34. Consistently, SLAMF1-silenced cells or SLAMF1low primary CLL cells were resistant to autophagy-activating therapeutic agents, such as fludarabine or the BH3 mimetic ABT-737. These results indicate that loss of SLAMF1 expression modulates genetic pathways regulating chemotaxis and autophagy and potentially affecting drug responses, thus providing a likely explanation for the unfavorable clinical outcome experienced by this patient subset.
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