Site Editor

Jennifer R. Brown, MD, PhD

Advertisement
Advertisement

AACR 2022: Is Loss of the AID Enzyme Linked to Progression of CLL?

By: Lauren Harrison, MS
Posted: Friday, April 15, 2022

Loss of the enzyme called activation-induced cytidine deaminase (AID) may lead to progression of B-cell chronic lymphocytic leukemia (CLL) through multiple pathways. This may explain why CLL with unmutated immunoglobulin genes is linked to a high proliferative rate that requires treatment. Chih-Chi A. Hu, PhD, of the University of Pennsylvania, Philadelphia, and colleagues presented these results at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 142/8).

Researchers generated an AID-deficient mouse model of AID and discovered that these mice die significantly earlier than mice with normal AID levels. The AID-deficient mice had higher percentages of germinal center B cells and increased infiltration of CLL cells into the lungs, liver, and peritoneal cavity. Both AID-deficient B cells and CLL cells downregulated the Smad1/S1PR2 signaling pathway, which normally serves to suppress tumors through restraining expansion of the germinal center.

The AID-deficient mice also showed higher levels of B-cell receptor signaling. This led researchers to investigate the IRE1α/XBP1s pathway. When compared with control cells, the AID-deficient cells responded to stressors with a higher endoplasmic reticulum stress response through the IRE1α/XBP1s pathway. This led to cells that were more resistant to the stressed conditions within the tumor microenvironment. According to the researchers, upregulation in stress response was not solely due to accelerated leukemic progression, because the B cells from AID-deficient mice also expressed high levels of XBP1s and were more responsive to treatment with pharmacologic stressors.

To translate these results to human CLL, the team used short hairpin RNA knockdown of AID in a human CLL line, which created an increased stress response. CLL cells from patients with wild-type immunoglobulin genes expressed higher levels of XBP1 mRNA than cells from patients with mutated CLL. Treatment of both mouse and human CLL cells with an S1PR2 agonist and an IRE1 inhibitor led to more apoptosis induction, which may be a novel therapeutic option worthy of further study in CLL.

Disclosure: For a full list of authors’ disclosures, visit abstractsonline.com.


By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.