November 17, 2011

Aliquots — research highlights from VUMC laboratories


FERM target for rare leukemia

Most patients diagnosed with adult T-cell leukemia/lymphoma (ATLL) – a rare, aggressive blood cancer – will die within a year of diagnosis. No currently available treatments alter the disease’s aggressive clinical course.

Utpal Davé, M.D., and colleagues are working to identify genes and pathways that drive or initiate ATLL. In the Oct. 6 issue of Blood, they report that JAK3 (a component of the IL-2 signaling pathway) may be a therapeutic target for this disease. Among 36 ATLL patients, Davé and colleagues identified four patients with mutations in the “FERM” domain of JAK3, which promoted activity of the enzyme and the downstream pathways that regulate cell growth. They also showed that cells containing mutant JAK3 were more sensitive to an existing JAK3 inhibitor (tofacitinib, which is currently in clinical trials for autoimmune disorders) than cells with wild-type JAK3.

The results underscore the importance of this pathway in ATLL and suggest that JAK3 may represent an important therapeutic target for this aggressive disease.

This research was supported by grants from the National Heart, Lung, and Blood Institute, the Doris Duke Charitable Foundation, the Leukemia & Lymphoma Society, the Vanderbilt-Ingram Cancer Center, a Monforton family grant, and the T. J. Martell Foundation.

Melissa Marino


Exercise fights fatty liver

Because exercise is known to stimulate the action of glucagon (a hormone that raises blood glucose levels) in the liver, Eric Berglund, Ph.D., David Wasserman, Ph.D., and colleagues examined the role of hepatic glucagon action in mice with diet-induced fatty liver. They found that exercise reversed fatty liver in wild type mice independent of weight loss. However, these changes were absent in mice lacking the hepatic glucagon receptor, demonstrating that hepatic glucagon action is an essential component of the exercise-induced reversal of fatty liver.

The results, published in the November issue of Diabetes, also suggest that therapies targeting glucagon action (under investigation as treatments for hyperglycemia in type 2 diabetes) may interfere with the ability of exercise to reverse fatty liver.

The research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases.

Melissa Marino


Drug’s impact on heart rhythm

To determine factors that affect QT prolongation by drugs, Prince Kannankeril, M.D., and colleagues measured QT intervals before and after administration of a known QT-prolonging drug (ibutilide) in healthy young volunteers. They report in the October issue of Heart Rhythm that prolongation of the QT interval does not correlate with the baseline (pre-drug) QT interval and does not differ between men and women. They found that overweight and obese subjects had a greater drug effect on the QT interval than subjects with normal or low body mass index.

The findings have implications for drug-induced long QT syndrome. They suggest that the change in the QT interval is more important than baseline values for assessing risk and that obese subjects are at particularly high risk.

This research was supported by grants from the National Center for Research Resources and the National Heart, Lung and Blood Institute.

Leigh MacMillan


Skeletal defects in genetic disorder

Neurofibromatosis type I, an inherited disorder caused by mutations in the NF1 gene, is characterized by nerve tissue and optic pathway tumors and by other clinical features including skeletal abnormalities. In an effort to understand how NF1 mutations cause bone lesions, Florent Elefteriou, Ph.D., and colleagues generated a mouse model lacking the NF1 gene in the progenitor cells that give rise to the limbs and axial (central) skeleton.

They report in the Oct. 15 issue of Human Molecular Genetics that mice missing NF1 in these progenitor cells have bone defects that are similar to patients with neurofibromatosis. They also demonstrate that a drug that blocks the RAS/ERK signaling pathway, which is activated in the absence of NF1, rescues a bone porosity defect in the mice.

The study provides a new mouse preclinical model for testing novel therapeutic approaches for neurofibromatosis and suggests that the RAS/ERK signaling pathway is a rational target for prevention of bony lesions in the disorder.

This research was supported with funding from the Department of Defense, the National Institute of Arthritis and Musculoskeletal and Skin Disease, and the Children’s Tumor Foundation.

Leigh MacMillan


We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to:

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012