Researchers found that some receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are important to the development of AML, providing a target for potential therapies.
"We showed that these receptors are expressed by AML cells and that they support the development of AML. Although counterintuitive, this result is consistent with the generally immune-suppressive and thus tumor-promoting roles of inhibitory receptors in the immune system," said Dr. Chengcheng "Alec" Zhang, Associate Professor of Physiology and Developmental Biology, and a member of the Harold C. Simmons Comprehensive Cancer Center. "These findings suggest that blocking ITIM-receptor signaling in combination with conventional therapies may represent a novel strategy for AML treatment."
AML is a type of blood and bone marrow cancer in which certain stem cells or progenitor cells fail to properly mature into healthy white blood cells and instead become abnormal red cells, called leukemia cells, according to the National Cancer Institute, part of the National Institutes of Health. Leukemia cells can build up in the bone marrow and blood so there is less room for healthy white blood cells, red blood cells, and platelets, which can result in infections, anemia, or bleeding. Leukemia cells also can spread outside the blood to other parts of the body, including the central nervous system, skin, and gums, according to the NCI. Symptoms of adult AML include fever, feeling tired, and easy bruising or bleeding.
The study, which appears in Nature Cell Biology, focused mainly on an ITIM-containing receptor called LAIR1.
Researchers found that deleting LAIR1 abolished leukemia development in several different mouse models of leukemia. They also identified an important pathway that sustains the survival and self-renewal of AML cells, the mechanism by which LAIR1 supports AML development.
"Our study suggests that current treatment options, including chemotherapy, may not efficiently target cancer stem cells because these inhibitory receptors enable the leukemia stem cells to survive conventional therapies, eventually resulting in tumor relapse," said Dr. Zhang, Michael L. Rosenberg Scholar in Medical Research. "The blockade of ITIM-receptor signaling may prove to be a novel, effective strategy for elimination of leukemia stem cells and lead to complete remission in patients."
Treatments for AML generally yield poor outcomes, especially for typical senior patients, Dr. Zhang noted. Despite continuous treatment, most AML patients relapse within 5 years, according to published outcome studies.
The medical need for new therapies for AML is further underscored by the fact that no new therapies for AML have been approved in over 30 years. There are more than 50 experimental agents in clinical trials for the treatment of AML, but only a few agents have yielded promising data to date, he noted.
"New molecular targets and therapeutic strategies are needed for AML treatment," he said.
The Zhang laboratory studies the roles of immune inhibitory receptors in stem cells and cancer. Dr. Zhang hopes to understand the molecular mechanisms that govern the fates of adult stem cells and cancer cells, and apply this knowledge to the development of new cell and antibody therapies for treating cancer and other diseases.
Researchers involved included Dr. Robert Collins, Professor of Internal Medicine and holder of the Sydney and J.L. Huffines Distinguished Chair in Cancer Research in Honor of Eugene Frenkel, M.D. and the H. Lloyd and Willye V. Skaggs Professorship in Medical Research; UT Southwestern postdoctoral researchers Xunlei Kang, Mi Deng and Zhigang Lu; former UT Southwestern researchers Changhao Cui, and Yuqi Fan; and researchers from the University of Texas MD Anderson Cancer Center, Oregon Health and Science University Knight Cancer Institute, the National Institute of Allergy and Infectious Diseases, the University of Texas Graduate School of Biomedical Sciences at Houston, and the Dalian University of Technology in China.
The researchers are supported by grants from the National Institutes for Health, the Leukemia & Lymphoma Society, the March of Dimes Foundation, the Robert A. Welch Foundation, When Everyone Survives Foundation, V Foundation for Cancer Research, the William Lawrence and Blanche Hughes Fund, National Cancer Institute, Susan G. Komen Foundation, National Institute of Allergy and Infectious Diseases, Ladies Leukemia League, Developmental Research Awards in Leukemia, Center for Inflammation and Cancer, IRG, Center for Genetics and Genomics, Sister Institution Network Fund and Physician Scientist Award of the University of Texas MD Anderson Cancer Center.
UT Southwestern's Harold C. Simmons Comprehensive Cancer Center is the only National Cancer Institute-designated cancer center in North Texas and one of just 68 NCI-designated cancer centers in the nation. The Simmons Cancer Center includes 13 major cancer care programs with a focus on treating the whole individual with innovative treatments, while fostering groundbreaking research that has the potential to improve patient care and prevention of cancer worldwide. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians.
The Simmons Cancer Center is among only 30 U.S. cancer research centers to be named a National Clinical Trials Network Lead Academic Participating Site, a prestigious new designation by the NCI, and the only Cancer Center in North Texas to be so designated. The designation and associated funding is designed to bolster the cancer center's clinical cancer research for adults and to provide patients access to cancer research trials sponsored by the NCI, where promising new drugs often are tested.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to about 92,000 hospitalized patients and oversee approximately 2.1 million outpatient visits a year.
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