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Melbourne, Australia

Huntington N.D.,Walter and Eliza Hall Institute
Immunology and Cell Biology | Year: 2014

Natural killer (NK) cells are the founding members of the innate lymphoid cell family and contribute to the rapid production of inflammatory mediators upon pathogen detection. The evolution of receptors for self major histocompatibility complex-I and stress-induced ligands also bestows upon NK cells an important effector role in the clearance of virus-infected and transformed cells. NK cells are dependent on the pleiotropic cytokine interleukin (IL)-15 for their development, differentiation and optimal function. Here I review the regulation of IL-15 in vivo, its role in driving NK cell differentiation and discuss the function of NK cell diversification with regard to innate immunity. © 2014 Australasian Society for Immunology Inc.


Blewitt M.,Walter and Eliza Hall Institute | Whitelaw E.,Queensland Institute of Medical Research
Cold Spring Harbor Perspectives in Biology | Year: 2013

Much of what we know about the role of epigenetics in the determination of phenotype has come from studies of inbred mice. Some unusual expression patterns arising fromendogenous and transgenic murine alleles, such as the Agouti coat color alleles, have allowed the study of variegation, variable expressivity, transgenerational epigenetic inheritance, parent-of-origin effects, and position effects. These phenomena have taught us much about gene silencing and the probabilistic nature of epigenetic processes. Based on some of these alleles, large-scale mutagenesis screens have broadened our knowledge of epigenetic control by identifying and characterizing novel genes involved in these processes. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Blewitt M.,Walter and Eliza Hall Institute
Cold Spring Harbor perspectives in biology | Year: 2013

Much of what we know about the role of epigenetics in the determination of phenotype has come from studies of inbred mice. Some unusual expression patterns arising from endogenous and transgenic murine alleles, such as the Agouti coat color alleles, have allowed the study of variegation, variable expressivity, transgenerational epigenetic inheritance, parent-of-origin effects, and position effects. These phenomena have taught us much about gene silencing and the probabilistic nature of epigenetic processes. Based on some of these alleles, large-scale mutagenesis screens have broadened our knowledge of epigenetic control by identifying and characterizing novel genes involved in these processes.


Tarlinton D.,Walter and Eliza Hall Institute
Current Biology | Year: 2012

Three recent papers provide striking insight into the mechanisms used to regulate B-cell differentiation. They demonstrate that B-cell fate choice can be stochastic, directed, inherited, or some combination of these, depending on the circumstances. The trick is going to be working out which is important when. © 2012 Elsevier Ltd.


Buchert M.,Walter and Eliza Hall Institute
Oncogene | Year: 2015

Various human malignancies are characterized by excessive activation of the Janus family of cytoplasmic tyrosine kinases (JAK) and their associated transcription factors STAT3 and STAT5. In the majority of solid tumors, this occurs in response to increased abundance of inflammatory cytokines in the tumor microenvironment prominently produced by infiltrating innate immune cells. Many of these cytokines share common receptor subunits and belong to the interleukin (IL)-6/IL-11, IL-10/IL-22 and IL-12/IL-23 families. Therapeutic inhibition of the JAK/STAT3 pathway potentially offers considerable benefit owing to the capacity of JAK/STAT3 signaling to promote cancer hallmarks in the tumor and its environment, including proliferation, survival, angiogenesis, tumor metabolism while suppressing antitumor immunity. This is further emphasized by the current successful clinical applications of JAK-specific small molecule inhibitors for the treatment of inflammatory disorders and hematopoietic malignancies. Here we review current preclinical applications for JAK inhibitors for the treatment of solid cancers in mice, with a focus on the most common malignancies emanating from oncogenic transformation of the epithelial mucosa in the stomach and colon. Emerging data with small molecule JAK-specific adenosine triphosphate-binding analogs corroborate genetic findings and suggest that interference with the JAK/STAT3 pathway may suppress the growth of the most common forms of sporadic colon cancers that arise from mutations of the APC tumor suppressor gene. Likewise inhibition of cytokine-dependent activation of the JAK/STAT3 pathway may also afford orthogonal treatment opportunities for other oncogene-addicted cancer cells that have gained drug resistance.Oncogene advance online publication, 18 May 2015; doi:10.1038/onc.2015.150. © 2015 Macmillan Publishers Limited

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