circPCMTD1 : A protein-coding circular RNA that regulates DNA damage response in BCR/ABL -positive leukemias

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• Circular RNAs (circRNAs) are emerging regulators of cellular processes, implicated in various diseases.
• The role of specific circRNAs, like circPCMTD1, in acute leukemias remains largely unexplored.

Purpose of the Study:

• To investigate the functional significance of circPCMTD1 in acute leukemias, particularly those with BCR-ABL translocations.
• To elucidate the molecular mechanisms by which circPCMTD1 influences leukemic cell behavior and survival.

Main Methods:

• Screening experiments to assess the impact of circPCMTD1 depletion on leukemic cell proliferation.
• Mass cytometry to identify downstream cellular events following circPCMTD1 modulation.
• In vivo studies using mouse models engrafted with human leukemic cells.
• Mechanistic investigations involving subcellular localization, ribosome association, and peptide product analysis.

Main Results:

• Depletion of circPCMTD1 significantly inhibited the proliferation of BCR-ABL-positive leukemic cells.
• circPCMTD1 depletion triggered an aberrant DNA damage response in leukemic cells.
• Targeting circPCMTD1 in vivo prolonged the survival of mice with Philadelphia chromosome-positive leukemia.
• circPCMTD1 was found to generate a peptide that enhances the BTR complex, increasing tolerance to genotoxic stress.

Conclusions:

• circPCMTD1 plays a critical role in promoting the proliferation and survival of acute leukemia cells, especially those with BCR-ABL.
• The circPCMTD1-derived peptide confers tolerance to genotoxic stress by modulating the BTR complex.
• circPCMTD1 represents a potential therapeutic target for acute leukemias harboring the Philadelphia chromosome.