Photo courtesy of UT
Southwestern Medical Center
Preclinical research suggests that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are important for the development of acute myeloid leukemia (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 Chengcheng Zhang, PhD, of UT Southwestern Medical Center in Dallas, Texas.
“These findings suggest that blocking ITIM-receptor signaling in combination with conventional therapies may represent a novel strategy for AML treatment.”
Dr Zhang and his colleagues reported their findings in Nature Cell Biology.
The team focused mainly on an ITIM-containing receptor called LAIR1. They found that deleting LAIR1 abolished leukemia in several different mouse models, without affecting normal hematopoiesis.
The investigators also identified a pathway that sustains the survival and self-renewal of AML cells, the mechanism by which LAIR1 supports AML development.
They said LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signaling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. And the LAIR1–SHP-1–CAMK1–CREB pathway sustains AML stem cells.
So the investigators believe that inhibiting the signaling initiated by LAIR1 and other ITIM-containing receptors could help us treat AML more effectively.
“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,” Dr Zhang said.
“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.”
