JCI online early table of contents: Sept. 13, 2010

Myeloproliferative neoplasms (MPN) comprise a family of blood cancers characterized by clonal expansion of a single blood cell type. Untreated, these cancers can progress to bone marrow failure and acute myeloid leukemia. Several groups have identified activating mutations in the JAK2 gene as associated with MPN; JAK2 inhibition has therefore emerged as approach to MPN therapy. Thus far, however, JAK2 inhibition strategies have had limited efficacy and have been accompanied by significant toxicity. In this paper, Ross Levine and his group at the Memorial Sloane Kettering Cancer Center, New York, describe an indirect approach to reducing JAK2 activity by pharmacologically targeting HSP90, a protein that stabilizes JAK2. Inhibiting HSP90 normalized blood counts and improved survival in two mouse models of MPN, and the treatment promoted JAK2 degradation in samples from MPN patients. The authors believe that targeting HSP90, perhaps in combination with JAK2 inhibition, may be the way forward in the treatment of patients with MPN.

TITLE:

HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans

AUTHOR CONTACT:

Ross L. Levine,
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 646.888.2796; Fax: 646.422.0890; E-mail: leviner@mskcc.org.

Gabriela Chiosis,
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: 646.888.2238; Fax: 646.422.0416; E-mail: chiosisg@mskcc.org.

James E. Bradner,
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Phone: 617.632.6629; Fax: 617.582.7370; E-mail: james_Bradner@dfci.harvard.edu.

Media contact
Kathleen Harrison
Memorial Sloane Kettering Cancer Center, New York, New York.
Phone: 212.639.3573; E-mail: harrisok@mskcc.org.

View this article at: http://www.jci.org/articles/view/42442?key=7ef55d4a4ce9ffed3af0

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disease that results in chronic kidney failure. Although the genes responsible for ADPKD have been identified (PKD1, PKD2), relatively little is known about how mutations in these genes promote cyst growth molecularly. In this paper, scientists at Children's Hospital in Boston, lead by Jordon Kreidberg, investigated the signaling pathways that go awry in the disease using mouse kidney epithelial cells in which Pkd1 was genetically deleted. They found that the protein c-Met was hyperactive in Pkd1-deficient cells, resulting in increased mTOR signaling, a pathway that had previously been linked to cyst formation. The increase in c-Met activity was related to sequestration of the protein c-Cbl in a cellular compartment known as the golgi, which increased c-Met protein stability. In support of a critical role for c-Met activity in disease progression, pharmacological inhibition of c-Met decreased mTOR activity and blocked cyst formation in a mouse model of ADPKD, leading the authors to suggest that c-Met is a potential therapeutic target in patients with ADPKD.

TITLE:

Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease

AUTHOR CONTACT:

Jordan Kreidberg,
Children's Hospital, Boston, Massachusetts, USA.
Phone: 617.919.2959; Fax: 617.730.0129;
E-mail: Jordan.Kreidberg@childrens.harvard.edu.

View this article at: http://www.jci.org/articles/view/41531?key=07331a5bc3d8a1998c3f

Kallmann syndrome is a developmental disorder characterized by hypogonadotropic hypogonadism (absence or defective function of the testes or ovaries) and a defective sense of smell as a result of an absence of olfactory bulbs, a condition known as arrhinencephaly. It has been suggested that hypogonadism is caused by failed embryonic migration of neurons producing gonadotropin-releasing hormone 1 (GnRH1) from the nasal epithelium to the forebrain. Now, Jean-Pierre Hardelin and colleagues, at the Pasteur Institute, France, have determined that failed embryonic migration of GnRH1-producing neurons is a common feature of several developmental disorders that include arrhinencephaly, specifically X-linked Kallmann syndrome, CHARGE syndrome, Patau syndrome (trisomy 13), and Edwards syndrome (trisomy 18).

Analysis of fetuses with these disorders indicated that there were few or no GnRH1-producing neurons in regions of the brain known as the preoptic and hypothalamic regions in arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. Instead, these cells accumulated in the fronto-nasal region of the brain, which is the first step of the GnRH neuronal migratory path. As interrupted olfactory nerve fibers were also detected in this region, the authors conclude that the failed migration of GnRH1-producing neurons observed in all four arrhinencephalic disorders studied occurs as a result of a primary embryonic failure of peripheral olfactory structures.

TITLE:

Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions

AUTHOR CONTACT:
Jean-Pierre Hardelin,
Institut Pasteur, Paris, France.
Phone: 33.1.45.68.88.91; Fax: 33.1.40.61.34.42;
E-mail: jean-pierre.hardelin@pasteur.fr.

View this article at: http://www.jci.org/articles/view/43699?key=c10e3ab8d55ad855aca1

The TGF-beta signaling pathway can be tumor suppressing or promoting depending on the tumor stage and context. One of the potential TGF-beta target genes involved in its dual effects of on cancer is hepatocyte growth factor (HGF), which, acting through c-Met, can lead to the proliferation, survival, invasion, and migration of tumor cells and angiogenesis in tumor stroma. In human squamous cell carcinomas (SCCs), the TGF-beta signaling pathway components Smad2 and Smad4 are often down regulated. In this issue of the JCI, Xiao-Jing Wang and colleagues, of the University of Colorado, Denver, investigated the role of this signaling pathway in skin cancer by chemically inducing cancer in mice that lacked Smad2 specifically in the skin. SCCs in these mice showed increased blood vessel density and increased levels of HGF. Further analysis revealed a repressive role for Smad2 in expression from the HGF gene, countered by an activating role for Smad4 on the same gene. The authors believe that their findings suggest that analysis of Smad expression in human tumors may be an important biomarker that will allow for the development of better targeted therapies in the future.

TITLE:

HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion

AUTHOR CONTACT:
Xiao-Jing Wang,
University of Colorado, Denver, Aurora, Colorado, USA.
Phone: 303.724.3001; Fax: 303.724.3712; E-mail: xj.wang@ucdenver.edu.

View this article at: http://www.jci.org/articles/view/43304?key=816259dd2d3d68f9ddd9

MyD88 is an adaptor protein in inflammatory signaling that has previously been implicated in inflammation-mediated tumor development. Renno Toufic and colleagues, at the University of Lyon, France, have now identified an additional role for MyD88 in cellular transformation, an event central to tumor formation, mediated by Ras, a common cancer-causing protein. They found that MyD88-deficient mice were resistant to Ras-dependent tumor formation, and that isolated MyD88-deficient cells were resistant to Ras-meditated transformation. Notably, this defect was not reliant on changes in inflammatory signaling. Further evidence linked MyD88 to human carcinogenesis, as it was highly expressed in a number of human tumor tissues, and reduction in MyD88 expression reduced proliferation rates in human tumor cell lines. This work suggests that in addition to its involvement in inflammatory pathways, MyD88 plays a cell-autonomous role in transformation.

TITLE:

Dual function of MyD88 in RAS signaling and inflammation, leading to mouse and human cell transformation

AUTHOR CONTACT:
Toufic Renno,
CNRS, Lyon, France.
Phone: 33.469.166.629; Fax: 33.469.166.660;
E-mail: renno@lyon.fnclcc.fr.

View this article at: http://www.jci.org/articles/view/42771?key=ee4b3bce94d50b626f16

The complement system is a key component of the innate immune system. However, chronic activation can result in deposition of complement activation products in the kidney, resulting in tissue injury. Dense Deposit Disease (DDD) is a severe kidney disease that has been associated with deficiency in factor H (fH), a negative regulator of the complement pathway. Consistent with this, studies in animal models have linked DDD to activation of complement. In this paper, Santiago Rodriguez de Córdoba and colleagues, at the Centro de Investigaciones Biológicas, Madrid, identified a familial case of DDD linked to a gain of function mutation in the C3 gene that rendered the protein resistant to cleavage and inactivation by fH. The authors believe that this finding will be important in the treatment of human patients, as it suggests that fH replacement will be ineffective in those patients with DDD that carry C3 mutations. Furthermore, this work reveals the structural properties of C3 that are relevant to its inactivation, and thus may be critical in the development of therapeutics.

TITLE:

Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation

AUTHOR CONTACT:
Santiago Rodríguez de Córdoba,
Centro de Investigaciones Biológicas, Madrid, Spain.
Phone: 34.918373112; Fax: 34.915360432; E-mail: SRdeCordoba@cib.csic.es.

View this article at: http://www.jci.org/articles/view/43343?key=10a2d12b59b663b040c1

The heart generates most of its energy by burning fats (or lipids) through a process called fatty acid oxidation (FAO). Despite this reliance on fat for energy, increased lipid accumulation in the heart can lead to reduced heart function in patients with obesity and type 2 diabetes. The proteins PPAR-alpha and PPAR-gamma are thought to play a role in promoting lipid accumulation and FAO in fat tissue, and increased expression and activation of PPAR-alpha and -gamma in the heart leads to cardiomyopathy, i.e., weakening of the heart muscle.

To analyze more fully the role of PPAR-alpha and –gamma in lipotoxic cardiomyopathy, Ira Goldberg and a team of scientists at Columbia University, New York, investigated heart function in mice in which PPAR-gamma was over-expressed in the heart (a model of cardiomyopthy) and PPAR-alpha had been genetically deleted. They found that deletion of PPAR-alpha improved heart function in this model, but surprisingly, this improvement was associated with increased levels of FAO and increased expression of genes involved in lipid storage. The improvement in heart function was related to a differential distribution of lipid into larger droplets, as well as reduced levels of cellular stress in the heart muscle. The researchers believe that these data demonstrate that increased lipid storage and FAO levels are not inherently toxic to the heart, and that targeting of these processes may represent a promising therapeutic strategy for lipotoxic cardiomyopathy.

TITLE:

PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation

AUTHOR CONTACT:
Ira J. Goldberg,
Columbia University, New York, New York, USA.
Phone: 212.305.5961; Fax: 212.305.3213; E-mail: ijg3@columbia.edu.
View this article at: http://www.jci.org/articles/view/40905?key=78f0274db36a17a0c8f1