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ITIM-Containing Receptor LAIR1 Inhibits Immune Response and Is Key to Development of Acute Myeloid Leukemia (AML); Blockade of This Signaling May Eliminate Leukemia Stem Cells and Lead to Complete Remission in AML Patients, Senior Author Suggests

University of Texas (UT) Southwestern Medical Center scientists have discovered that a certain class of receptors that inhibit the immune response are crucial for the development of acute myeloid leukemia (AML), the most common acute leukemia affecting adults. The researchers found that some receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are important to the development of AML, providing a new 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 at UT Southwestern. “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 (NCI), part of the National Institutes of Health (NIH). 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 new study, which was published online on April 27, 2015 in Nature Cell Biology, focused mainly on an ITIM-containing receptor called LAIR1. The article is titled “The ITIM-Containing Receptor LAIR1 Is Essential for Acute Myeloid Leukemia Development.” Researchers found that deleting LAIR1 abolished leukemia development in several different mouse models of leukemia. The scientists 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,” Dr. Zhang 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 Dr. Xunlei Kang, Dr. Mi Deng, and Dr. Zhigang Lu; former UT Southwestern researchers Dr. Changhao Cui and Dr. 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 (NIAID), the University of Texas Graduate School of Biomedical Sciences at Houston, and the Dalian University of Technology in China.

Image shows cells stained with fluorescent anti-LAIR1 antibody.

[Press release] [Nature Cell Biology abstract]