The Feature of MALT1-A20-NF-κB Expression Pattern Provide Important Insights Into the Therapeutic Benefit for T-ALL

Abstract 4810

The knowledge of oncogenic signaling pathways of T-cell acute lymphoblastic leukemia (T-ALL) is still limited. Constitutive aberrant activation of NF-κB signaling has been detected in various lymphoid malignancies and plays a key role in the development of these malignancies. The zinc finger-containing protein A20 (also known as Tumor Necrosis Factor Alpha-Induced Protein 3 or TNFAIP3) is a central regulator of multiple NF-κB activating signaling cascades. A20 is inactivated and results in constitutive NF-κB activation in tumor cells. A20 is now known to act as a crucial tumor suppressor in various hematological malignancies like lymphomas. MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) plays a critical role in the regulation of NF-κB pathways, and mediated rapid proteolytic cleavage and inactivation of A20. To further characterize the function of these signal molecules, we analyzed the expression levels of A20, NF-κB and MALT1 genes in peripheral blood mononuclear cells (PBMCs) of 19 patients newly diagnosed with T-ALL (aged 4–70 years, median 25), and investigated the relationship between the aberrant expressions of these genes and T-ALL. Twenty-nine healthy individuals (aged 20–57, median 28) served as controls. We found that the expression levels of A20 in T-ALL patients (6.057±5.275) were significantly lower than healthy group (9.865±5.370) (P=0.020), while the expression levels of NF-κB (0.560±0.425) and MALT1 (2.712±3.127) in T-ALL patients were significantly higher than healthy group (0.337±0.311, 0.713±0.464) (P=0.041, P=0.001). The expression levels of A20 had a significant negative correlation with the expression of MALT1 (r=−0.628, P=0.009), and the reduced levels of A20 had a positive correlation with the increased expression of NF-κB in T-ALL (r=0.588, P=0.017). In conclusion, the overexpression of MALT1 in T-ALL causes constitutively cleavage and inactivation of A20 to enhance NF-κB signaling, and may contribute to the pathogenesis of T-ALL. Thus, MALT1 may consider as a potentially attractive target for the development of T-ALL therapeutics.