DDX3X Abnormalities Promote CLL Progression by Facilitating NOTCH1 mRNA Translation

Abnormalities in the driver gene DDX3X on the X chromosome are common in chronic lymphocytic leukemia (CLL) and associated with poor prognosis, according to a recent study.

The study’s researchers, led by Yi Miao, MD, of the First Affiliated Hospital of Nanjing Medical University in China, also identified the effect and mechanism of DDX3X dysregulation on tumorigenesis and development of CLL by in vitro experiments.

Dr. Miao and colleagues presented the study as an abstract at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

The researchers performed next-generation sequencing on 402 patients with CLL or small lymphocytic lymphoma (SLL) and found that patients with DDX3X mutations had more adverse prognostic indicators: unmutated IGHV (88.2% vs 48.6%; P=.002), 17p deletion (42.9% vs 11.4%; P=.041), and 11q deletion (46.7% vs 15.7%; P=.006), suggesting that dysregulation of DDX3X contributes to the progression of CLL and SLL.

To evaluate the mechanisms by which DDX3X deletion affects CLL, the researchers detected key signaling pathways in the tumorigenesis and development of CLL in DDX3X knockout and control cells. They found increased expression of NOTCH1 and its downstream target proteins in DDX3X knockout cells, indicating that loss of DDX3X activated the NOTCH1 pathway. A dual-luciferase reporter assay showed enhanced activity of NOTCH1 5′ UTR in DDX3X knockout cells, further suggesting that DDX3X may regulate translation of NOTCH1 messenger RNA (mRNA) by binding to the 5′ UTR. Finally, using polysome profiling, they demonstrated that DDX3X knockout resulted in increased NOTCH1 mRNA in polysome fractions, confirming that loss of DDX3X function facilitates NOTCH1 mRNA translation.

“DDX3X dysregulation is involved in the progression of CLL by facilitating NOTCH1 mRNA translation through binding to the 5′ UTR,” the authors concluded.

Reference

Miao Y, Zhang J, Zhu H, Li J. Loss of DDX3X function promotes CLL progression by facilitating NOTCH1 mRNA translation. Abstract #83. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.