NSUN2-FOSB reciprocity facilitates leukemogenesis in an m5C-dependent manner by increasing BCL2L1 expression

Area of Science:

• Molecular Biology
• Cancer Research
• Hematology

Background:

• The role of NOP2/Sun RNA methyltransferase family member 2 (NSUN2) in normal hematopoiesis and leukemogenesis is not well understood.
• NSUN2 catalyzes 5-methylcytosine (m5C) modifications on RNA, influencing mRNA stability.
• NSUN2 is found to be upregulated in acute myeloid leukemia (AML) patient samples.

Purpose of the Study:

• To investigate the role of NSUN2 in acute myeloid leukemia (AML) pathogenesis.
• To explore the potential of NSUN2 as a therapeutic target in AML.

Main Methods:

• NSUN2 knockdown (KD) and genetic ablation in murine MLL-AF9 (MA9)-transformed AML models.
• Analysis of leukemia stem cell (LSC) self-renewal, proliferation, apoptosis, and colony formation.
• Investigation of NSUN2's mechanism involving FosB proto-oncogene (FOSB) mRNA stabilization and B-cell lymphoma-2-like protein 1 (BCL2L1) expression.

Main Results:

• NSUN2 knockdown/ablation impaired AML cell proliferation, induced apoptosis, reduced colony formation, and prolonged survival in a murine AML model.
• NSUN2 deficiency impaired LSC self-renewal while sparing normal hematopoiesis.
• NSUN2 stabilizes FOSB mRNA via m5C modification, upregulating FOSB, which in turn transcriptionally activates NSUN2, creating a feedforward loop. FOSB also promotes BCL2L1 expression.

Conclusions:

• NSUN2 plays a critical role in AML leukemogenesis through an m5C-dependent mechanism involving the FOSB-BCL2L1 axis.
• The NSUN2-FOSB-BCL2L1 pathway represents a novel therapeutic target for AML treatment.
• Targeting NSUN2 could offer a selective approach to AML therapy, sparing normal hematopoiesis.