HTLV-1 HBZ inhibits DHX9 to reprogram circRNA biogenesis in ATLL

Area of Science:

• Molecular Biology
• Virology
• Cancer Research

Background:

• Human T-cell Leukemia Virus type 1 (HTLV-1) causes Adult T-cell Leukemia/Lymphoma (ATLL).
• The viral oncoprotein HBZ is known to alter gene transcription in ATLL.
• HBZ's role in post-transcriptional regulation, specifically concerning circular RNAs (circRNAs), is not well understood.

Purpose of the Study:

• To investigate the mechanism by which HBZ reprograms circRNA biogenesis in ATLL.
• To identify specific circRNAs regulated by HBZ and their role in leukemic cell survival.
• To elucidate the interaction between HBZ and host factors in regulating circRNA production.

Main Methods:

• Comprehensive circRNA profiling across different ATLL subtypes.
• Functional analyses of circAFF2(3) expression on leukemic cell survival.
• Mechanistic studies involving HBZ, DHX9, and circRNA biogenesis using endogenous and synthetic circRNAs.

Main Results:

• Extensive circRNA remodeling was observed in ATLL, with distinct patterns in aggressive subtypes.
• circAFF2(3) was significantly upregulated in aggressive ATLL and promoted leukemic cell survival.
• HBZ inhibits DHX9 helicase activity at specific RNA structures, promoting the accumulation of DHX9-sensitive circRNAs like circAFF2(3).

Conclusions:

• HTLV-1 utilizes HBZ to reprogram circRNA biogenesis, contributing to ATLL pathogenesis.
• The HBZ-DHX9 interaction represents a novel post-transcriptional regulatory axis in ATLL.
• Targeting the HBZ-DHX9 axis may offer new therapeutic strategies for ATLL.