EDITOR'S PICK: Targeting the more lethal form of the cancer rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is an aggressive muscle cancer that mostly affects children. The most common forms of RMS are embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS). Although ARMS is less common than ERMS, it is associated with a much higher rate of mortality. A therapy tailored to the ARMS form of RMS is therefore badly needed. A team of researchers, at the Hospital for Sick Children, Toronto, and Monash Institute of Medical Research, Australia, has now provided hope that it might be possible to develop such a therapy by showing that the protein ILK promotes the growth of ARMS cells, whereas it suppresses the growth of ERMS cells.
The team, led by David Malkin and Gregory Hannigan, determined that the signaling protein JNK mediated these differing effects of ILK. Knocking down expression of ILK in ERMS cells induced activation of JNK and promoted tumor cell growth both in vitro and when the cells were transplanted into immunodeficient mice. Conversely, knocking down expression of ILK in ARMS cells abrogated both JNK signaling and tumor cell growth. Further analysis revealed that the protein product of the fusion gene that characterizes ARMS downregulated JNK1 expression, providing mechanistic insight into the opposing roles of ILK in ARMS and ERMS. The authors therefore suggest it should be possible to identify patients with ARMS who would benefit from an anticancer therapeutic that targets ILK.
In an accompanying commentary, Charles Keller and colleagues concur with the authors that targeting ILK might provide a therapeutic strategy tailored to the treatment of ARMS. However, they caution that further studies are needed, in part because of the high rate of misdiagnosis of ARMS versus ERMS.
TITLE: JNK1 determines the oncogenic or tumorsuppressive activity of the integrin-linked kinase in human rhabdomyosarcoma
AUTHOR CONTACT:
David Malkin
Hospital for Sick Children, Toronto, Ontario, Canada.
Phone: (416) 813-5348; Fax: (416) 813-5327; E-mail: david.malkin@sickkids.ca.
Gregory E. Hannigan
Monash Institute of Medical Research, Melbourne, Victoria, Australia.
Phone: 61-03-9594-7245; Fax: 61-03-9594-7252; E-mail: greg.hannigan@med.monash.edu.au.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37958
ACCOMPANYING COMMENTARY
TITLE: Integrin-linked kinase: both Jekyll and Hyde in rhabdomyosarcoma
AUTHOR CONTACT:
Charles Keller
University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Phone: (210) 562-9062; Fax: (210) 562-9014; E-mail: kellerc2@uthscsa.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39457
NEUROBIOLOGY: What's DAT? Deficiency in mature DAT protein linked to parkinsonin disorder
Variants of the SLC6A3 gene, which is responsible for generating the human protein dopamine transporter (DAT), have been linked to attention deficit hyperactivity and bipolar disorders. Now, Eamonn Maher and colleagues, at the University of Birmingham, United Kingdom, have provided evidence that mutations in SLC6A3 are associated with a parkinsonian disorder, infantile parkinsonism-dystonia.
In the study, analysis of two unrelated consanguineous families in which some individuals had infantile parkinsonism-dystonia determined that individuals with the disorder had mutations in both copies of their SLC6A3 gene. Although the mutations were different in the two families, they both were loss-of-function mutations, as evidenced by a dramatic reduction in the levels of the mature form of the DAT protein. The clear association between these mutations and infantile parkinsonism-dystonia led the authors to suggest that mutations in SLC6A3 might be linked with other movement disorders associated with parkinsonian and/or dystonic feature. In addition, Craig Blackstone, at the National Institute of Neurological Disorders and Stroke, Bethesda, suggests in an accompanying commentary that if more disorders are linked to SLC6A3 mutations they could be classified as "transportopathies".
TITLE: Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia
AUTHOR CONTACT:
Eamonn R. Maher
University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Phone: 44-121-627-2741; Fax: 44-121-414-2538; E-mail: e.r.maher@bham.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39060
ACCOMPANYING COMMENTARY
TITLE: Infantile parkinsonism-dystonia: a dopamine "transportopathy"
AUTHOR CONTACT:
Craig Blackstone
National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Phone: (301) 451-9680; Fax: (301) 480-4888; E-mail: blackstc@ninds.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39632
VIROLOGY: How viral infection can protect from type 1 diabetes
Type 1 diabetes is caused by immune system–mediated destruction of insulin-producing beta-cells in the pancreas. It is known that infection with a virus can induce an immune response that damages beta-cells or a response that protects an individual from type 1 diabetes. However, the mechanisms by which viruses can have such divergent effects are not well understood. A team of researchers, at La Jolla Institute for Allergy & Immunology, La Jolla, has now provided some insight into this issue by showing that in a mouse model of type 1 diabetes, viruses that do not damage beta-cells provide protection from the autoimmune disease.
The team, led by Christophe Filippi and Matthias von Herrath, observed that infection with either Coxsackie virus B3 or lymphocytic choriomeningitis virus delayed the onset and reduced the incidence of disease in the mouse model of type 1 diabetes. Further analysis revealed a synergistic underlying protective mechanism: levels of the protein PD-L1 were transiently upregulated on immune cells known as lymphoid cells, and there was an increase in the number of CD4+CD25+ Tregs and an increase in their ability to produce the immunomodulatory factor TGF-beta. In an accompanying commentary, Terry Strom, at Beth Israel Deaconess Medical Center, Boston, discusses these mechanisms in further detail.
TITLE: Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice
AUTHOR CONTACT:
Christophe M. Filippi
La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.
Phone: (858) 752-6500; Fax: (858) 752-6993; E-mail: christophe@liai.org.
Matthias G. von Herrath
La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.
Phone: (858) 752-6500; Fax: (858) 752-6993; E-mail: matthias@liai.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38503
ACCOMPANYING COMMENTARY
TITLE: Can childhood viral infection protect from type 1 diabetes?
AUTHOR CONTACT:
Terry B. Strom
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: (617) 735-2880 Fax: (617) 667-0923; E-mail: tstrom@bidmc.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39565
NEPHROLOGY: Complex characteristics: insight into the content of the hallmark protein complexes in IgA nephropathy
Jan Novak and colleagues, at the University of Alabama, Birmingham, have provided new insight into the protein complexes that characterize the kidney disease IgA nephropathy. In an accompanying commentary, Richard J. Glassock, at UCLA David Geffen School of Medicine, Los Angeles, suggests that these data "may lead to new methods of diagnosis, monitoring, and therapy for patients with IgA nephropathy".
The protein complexes that characterize IgA nephropathy are aggregates of immune molecules known as antibodies (Ig molecules), specifically, galactose-deficient IgA1 and glycan-specific IgG. In the study, the molecular properties of the IgG antibodies were determined using cell lines derived from patients with IgA nephropathy. When IgG specific for galactose-deficient IgA1 were analyzed at the molecular level, a variant specific for patients with IgA nephropathy was discovered, there was an A to S substitution in a region of the IgG molecule known as the CDR3 of the variable region of the heavy chain. Reverting the S back to A through molecular engineering reduced the binding of recombinant IgG to galactose-deficient IgA1, indicating its importance for generating the protein complexes associated with IgA nephropathy. As the authors developed a method to easily detect the glycan-specific IgG antibody they identified in individuals with IgA nephropathy and found that they could reliably determine whether large numbers of individuals had IgA nephropathy, they suggest that these antibodies might be disease-specific markers of clinical utility.
TITLE: Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity
AUTHOR CONTACT:
Jan Novak
University of Alabama at Birmingham, Birmingham, Alabama, USA.
Phone: (205) 934-4480; Fax: (205) 934-3894; E-mail: jannovak@uab.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38468
ACCOMPANYING COMMENTARY
TITLE: Analyzing antibody activity in IgA nephropathy
AUTHOR CONTACT:
Richard J. Glassock
UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Phone: (949) 388-8885; Fax: (949) 388-8882; E-mail: glassock@cox.net.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39189
Journal
Journal of Clinical Investigation