EDITOR'S PICK: Unraveling why children with Down syndrome have increased leukemia risk
Children with Down syndrome (DS) have an increased risk of developing leukemia, in particular acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Through their studies in a mouse model of DS, a team of researchers led by John Crispino, at Northwestern University, Chicago, has now identified a potential explanation as to why children with DS are at increased risk of AMKL. In doing so, they have also identified a candidate therapeutic target.
DS is a genetic condition in which a person has an extra copy of chromosome 21 (they have 3 copies rather than 2). It is not clear, however, which genes on chromosome 21 are responsible for the increased risk of developing leukemia observed in children with DS. Crispino and colleagues found that increased expression of the protein templated by the chromosome 21 gene Dyrk1a promotes AMKL in a mouse model of DS. Interestingly, an inhibitor of DYRK1A activity inhibited the in vitro growth of AMKL cells lines from individuals with DS. Crispino and colleagues therefore suggest that developing small-molecule inhibitors of DYRK1A activity may have therapeutic potential for DS-AMKL. Shai Izraeli and Yehudit Birger, at Sheba Medical Center, Israel, second this idea in an accompanying commentary.
TITLE: Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome
AUTHOR CONTACT:
John D. Crispino
Northwestern University, Chicago, Illinois, USA.
Phone: 312.503.1504; Fax: 312.503.0189; E-mail: j-crispino@northwestern.edu.
View this article at: http://www.jci.org/articles/view/60455?key=ebdcc7eb0722a8d27c0b
ACCOMPANYING COMMENTARY
TITLE: DYRK1A in Down Syndrome: an oncogene or tumor suppressor?
AUTHOR CONTACT:
Shai Izraeli
Edmond and Lily Safra Children Hospital, Sheba Medical Center, Tel Hashomer, Israel.
Phone: 972.3.5305943; Fax: 972.3.530.5942; E-mail: sizraeli@sheba.health.gov.il.
View this article at: http://www.jci.org/articles/view/62372?key=3ae146d8c86858ca1679
EDITOR'S PICK: Uncovered: genetic cause of complex disease seen in Irish Traveller community
Two independent groups of researchers — one led by Adrian Clark, at Queen Mary University of London, United Kingdom; and the other led by Jean-Laurent Casanova, at The Rockefeller University, New York — have now identified the disease-causing gene in patients with a complex inherited syndrome most commonly observed in the Irish Traveller community. As noted by Jordan Orange, at the University of Pennsylvania School of Medicine, Philadelphia, in an accompanying commentary, the new data provide deep mechanistic insight into a complex human condition and expand our understanding of the human immune and endocrine systems, both of which are disrupted in patients.
Within the Irish Traveller community, several families have been found to suffer from an inherited condition characterized by failure of the adrenal glands to produce adequate amounts of steroid hormones, abnormal development (in particular, retarded growth), and a deficiency in immune cells known as NK cells. Both groups of researchers found that mutations in the MCM4 gene are responsible for this complex inherited condition. The MCM4 gene is responsible for templating a protein that is required for DNA to replicate itself, something that happens every time a cell divides. Consistent with this, both groups of researchers found that the MCM4 mutations associated with disease caused genomic instability, something that they suggest might possibly put affected individuals at increased risk for cancer.
TITLE: MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans
AUTHOR CONTACT:
Adrian J.L. Clark
Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Phone: 44.20.7882.6202; Fax: 44.20.7882.6197; E-mail: a.j.clark@qmul.ac.uk.
View this article at: http://www.jci.org/articles/view/60224?key=cb4664b3464dffe5841c
ACCOMPANYING ARTICLE
TITLE: Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency
AUTHOR CONTACT:
Jean-Laurent Casanova
The Rockefeller University, New York, New York, USA.
Phone: 212.327.7331; Fax: 212.327.7330; E-mail: jean-laurent.casanova@rockefeller.edu.
View this article at: http://www.jci.org/articles/view/61014?key=9c3e63bab008bc523ccd
ACCOMPANYING COMMENTARY
TITLE: Unraveling human natural killer cell deficiency
AUTHOR CONTACT:
Jordan S. Orange
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 267.426.5622; Fax 267.426.0947; E-mail: orange@upenn.edu.
View this article at: http://www.jci.org/articles/view/62620?key=7b2cf2771a25813f75d8
CARDIOLOGY: Popeye proteins: providing strength to the beat of the heart
The rhythm of the heart beat is dictated by electrical impulses initiated by a small number of specialized heart muscle cells (pacemaker cells) that are located together in a small area of the wall of the heart called the sinus node. Many elderly individuals have a dysfunctional sinus node, which causes inappropriate heart rates, and require surgical implantation of a pacemaker. Despite the fact that in the United States alone approximately $2 billion is spent each year on such surgeries, little is known about the molecular causes underlying dysfunctional pacemaking in the elderly. Now, a team of researchers led by Thomas Brand, at the University of Würzburg, Germany, has identified a role for the Popeye domain containing proteins Popdc1 and Popdc2 in regulating pacemaking in the heart of stressed mice. Key to this conclusion was the observation that elderly mice lacking either Popdc1 or Popdc2 suffered from severe sinus node dysfunction when subjected to physical or mental stress. Brand and colleagues therefore suggest that the Popdc1/2-deficient mice will be useful to precisely establish the molecular causes underlying dysfunctional pacemaking in the elderly and could aid in the development of therapeutic strategies. Bastiaan Boukens and Vincent Christoffels, at the Academic Medical Center, The Netherlands, concur with these suggestions in an accompanying commentary.
TITLE: Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice
AUTHOR CONTACT:
Thomas Brand
Imperial College London, Harefield, United Kingdom.
Phone: 44.1895.453.826; Fax: 44.1895.828.900; E-mail: t.brand@imperial.ac.uk.
View this article at: http://www.jci.org/articles/view/59410?key=857a5a162b573df1beab
ACCOMPANYING COMMENTARY
TITLE: Popeye proteins: muscle for the aging sinus node
AUTHOR CONTACT:
Vincent M. Christoffels
Academic Medical Center, Amsterdam, The Netherlands.
Phone: 31.20.5667821. Fax: 31.20.6976177; E-mail: v.m.christoffels@amc.uva.nl.
View this article at: http://www.jci.org/articles/view/62588?key=29bba7ad5a6ed176334e
IMMUNOLOGY: Protective antifungal immunity in the absence of a fully functional immune system
Individuals whose immune system is compromised (e.g., AIDS patients, who have few immune cells known as CD4+ T cells) are at increased risk of developing fungal infections that normally do not affect humans. The incidence of such infections, and thus the need for antifungal vaccines, is increasing worldwide. However, there are currently no vaccines against fungi. One problem is that it is not clear whether vaccines will be able to induce protective immunity in patients with a compromised immune system. However, Bruce Klein and colleagues, at the University of Wisconsin School of Medicine and Public Health, Madison, have now generated data in mice that indicate that an antifungal vaccine can induce and maintain protective antifungal immunity (in the form of memory CD8+ T cells) in the absence of CD4+ T cells. These data have clear implications for the development of antifungal vaccines that target CD8+ T cells to induce protective immunity in immunocompromised patients.
TITLE: Protective antifungal memory CD8+ T cells are maintained in the absence of CD4+ T cell help and cognate antigen in mice
AUTHOR CONTACT:
Bruce Klein
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Phone: 608.263.9217; Fax: 608.262.8418; E-mail: bsklein@wisc.edu.
View this article at: http://www.jci.org/articles/view/58762?key=04f9b46252bc14958ab1
GASTROENTEROLOGY: Stemming the tide of microvillus inclusion disease
The lining of our intestines is continuously being replenished by self-renewing stem cells located in the wall of the intestines. However, the molecular mechanisms that regulate intestinal stem cell division and function are not well defined. A team of researchers led by Nan Gao, at Rutgers University, Newark, has now determined that the signaling proteins Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and generation of new intestinal lining cells in mice. Interestingly, the intestines of mice lacking Cdc42 in their intestinal lining cells were reminiscent of those of individuals with microvillus inclusion disease (MVID), a devastating congenital intestinal disorder that results in severe nutrient deprivation. Gao and colleagues therefore suggest that their data indicate that stem cell–based approaches could be beneficial to infants with MVID, which is often lethal.
TITLE: Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice
AUTHOR CONTACT:
Nan Gao
Rutgers University, Newark, New Jersey, USA.
Phone: 973.353.5523; Fax:
973.353.5518; E-mail: ngao@andromeda.rutgers.edu.
View this article at: http://www.jci.org/articles/view/60282?key=e6c05c15d90543d9b467
Journal
Journal of Clinical Investigation