UCSF Journal Club
Recent research by UCSF scientists
Alexandra Greer
Science editor
CANCER BIOLOGY: BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Duy, C. et al.(Müschen). Nature. 473(7347):384-8.
BCR-ABL1 is a mutation involving the breakage of chromosomes 9 and 22 at the ABL1 and BCR genes and an incorrect reattachment that results in constituitive activity of the ABL1 gene - a kinase that promotes cell replication and inhibits DNA repair mechanisms. This mutation causes almost all chronic myelogenous leukemias (CML) and a significant portion of acute lymphoblastic leukemias (ALL). Because of the ubiquity of the BCR-ABL1 mutation, tyrosine kinase inhibitors (TKIs) that inhibit the mutant ABL1 are a frontline medication against these types of leukemia. Despite their usefulness, however, these drugs often do not eradicate the cancer, resulting in additional morbidity and mortality. In this paper, researchers wanted to identify how these cancers avoid eradication by TKIs. They found that BCL6, which promotes cell survival by inhibiting the p53-mediated DNA damage response, is involved in a positive-feedback loop initiated by cancer treatment that causes increased survival of the cancer. By adding the BCL6 inhibitor RI-BPI, the researchers were able to eradicate BCR-ABL1-induced leukemia in mice and avoid relapse due to incomplete killing of the cancer.
NEUROSCIENCE: Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino Acid transporter 3 expression. Escartin, C. et al. (Swanson). Journal of Neuroscience. 31(20):7392-401.
Oxidative stress due to neurological disorders such as Parkinson’s or strokes can result in neuronal death and brain damage. In the brain, neurons protect themselves from oxidative damage through the production of glutathione (GSH), a tripeptide antioxidant. While it is known that astrocytes can induce production of GSH in neurons of the brain, it has not been shown by what specific mechanism this occurs. In this paper, researchers show the mechanism behind GSH production in neurons following activation by astrocytes. Oxidative stress, through reactive oxygen species (ROS), activates astrocytes to produce GSH and secrete it into the extracellular matrix. Outside of the cell, GSH is cleaved into its peptide fragments including cysteine. At the same time in neurons, ROS induces the transcription of a cysteine transporter, allowing uptake of the peptide into the cell. With increased cysteine in the neurons, they can now make GSH themselves, thereby protecting themselves from oxidative damage.
IMMUNOLOGY: Interplay between CD8α Dendritic Cells and Monocytes in Response to Listeria monocytogenes Infection Attenuates T Cell Responses. Kapadia, D.; Sadikovic, A.; Vanloubbeeck, Y.; Brockstedt, D.; Fong, L. PLoS One. 6(4):e19376.
Dendritic cells (DCs) are a type of immune cell that serve to orchestrate the adaptive immune response: they present proteins to T-cells, thereby activating them and priming the immune system to respond to invading pathogens expressing those same proteins. Different types of DCs have different specialties: some are specialized in presenting proteins to cytotoxic, cd8+ T-cells, while others are more efficient in presenting proteins to T-helper (cd4+) cells. In Listeria monocytogenes infection, cd8+ DCs are both the predominantly infected DC subtype and are necessary for a productive immune response. In this paper, researchers examined the interplay between cd8+ DCs, cd11b+ DCs, and monocytes in Listeria infection. They found that while monocytes increased the amount of the inflammatory cytokines IL-12p70 and TNFα secreted by DCs, monocytes also decreased the ability for those DCs to activate T-cells. The authors propose that this may either serve as a monocyte-controlled way to control the spread of infectious Listeria within the cd8+ DC subset, or as a way for Listeria to avoid being killed with a strong cytotoxic cd8+ T-cell response initiated by the cd8+ DC subset.
IMMUNOLOGY: Genetic analysis of basophil function in vivo. Sullivan, B.M. et al. (Locksley). Nature Immunology. 12(6):527-35.
In the past year or two, a significant controversy in the field of immunology has developed over the role of basophils in the immune response. Some laboratories have asserted that basophils essentially usurp the role that DCs usually play in activating T-cells and orchestrating the immune response by presenting antigen and activating T-cells. This was a very surprising conclusion that led some to conclude that DCs were not as central to the immune response as they had been assumed to be for decades. As other laboratories were quick to point out, however, the original reports about basophils had used flawed models that involved incomplete depletion of basophils or DCs. In this paper, researchers have developed a genetic method of basophil depletion in a mouse, thereby providing a way to determine whether they are useful in generating a T-cell response against allergen or parasite infection. Unlike the original basophil findings, researchers here found that basophils were dispensable for the development of a T-cell response, and that DCs remain indispensable in the orchestration of adaptive immunity.
For comments or paper suggestions, please email Alex at Alexandra.Greer@ucsf.edu.
This article appeared in the May 26, 2011 issue of Synapse.
