Clec12a is required for the pathogenesis of NUP98::NSD1 AML

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• NUP98::NSD1 fusions are common in acute myeloid leukemia (AML) and linked to poor treatment outcomes.
• Existing treatments for NUP98::NSD1 AML are often ineffective, necessitating novel therapeutic targets.
• CLEC12A is a cell surface receptor differentially expressed in leukemic stem cells (LSCs).

Purpose of the Study:

• To investigate the role of CLEC12A in NUP98::NSD1-driven AML.
• To assess the therapeutic potential of targeting CLEC12A in NUP98::NSD1 AML.

Main Methods:

• Overexpression of CLEC12A was confirmed in NUP98::NSD1 patient and murine AML cells.
• CRISPR/Cas9 was used to deplete Clec12a expression in NUP98::NSD1+NRASG12D cells.
• In vitro apoptosis and colony formation assays were performed.
• In vivo leukemic engraftment and survival studies were conducted in a murine model.

Main Results:

• CLEC12A was significantly overexpressed in NUP98::NSD1 AML.
• Depletion of Clec12a led to increased apoptosis and reduced colony formation in vitro.
• Clec12a deletion significantly reduced leukemic engraftment and improved survival in vivo.

Conclusions:

• CLEC12A is highly expressed in NUP98::NSD1 AML and contributes to leukemogenesis.
• Targeting CLEC12A demonstrates therapeutic potential for NUP98::NSD1 AML.
• Further exploration of CLEC12A as a treatment target is warranted.