ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia

Area of Science:

• Molecular Biology
• Cancer Research
• Hematology

Background:

• The molecular drivers of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) are not fully understood.
• While spliceosome gene mutations are known to contribute to leukemic transformation, RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes also generates isoform diversity and regulates stem cell maintenance.

Purpose of the Study:

• To investigate the role of ADAR enzymes, specifically ADAR1, in the progression and self-renewal of leukemia stem cells in chronic myeloid leukemia (CML).
• To explore ADAR1 as a potential therapeutic target for LSC detection and eradication strategies.

Main Methods:

• Whole-transcriptome sequencing of normal, chronic phase, and blast crisis CML progenitors.
• Lentiviral overexpression of ADAR1 p150.
• Serial transplantation assays and short hairpin RNA (shRNA) knockdown studies.

Main Results:

• Increased expression of the IFN-γ pathway, BCR-ABL amplification, and the ADAR1 p150 isoform were observed during CML progression, correlating with increased RNA editing.
• ADAR1 p150 overexpression induced malignant reprogramming of myeloid progenitors, promoted PU.1 expression, and led to a misspliced form of GSK3β implicated in LSC self-renewal.
• ADAR1 knockdown significantly impaired the in vivo self-renewal capacity of blast crisis CML progenitors.

Conclusions:

• ADAR1 p150 plays a critical role in the malignant reprogramming and self-renewal of leukemia stem cells in CML.
• These findings provide a strong rationale for developing ADAR1-based strategies for LSC detection and eradication.