The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression

Area of Science:

• Molecular Biology
• Oncology
• RNA Modifications

Background:

• N6-methyladenosine (m6A) is the most abundant mRNA modification and plays a key role in acute myelogenous leukemia (AML) pathogenesis.
• Identifying regulators of m6A in AML is crucial for understanding disease biology and developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the role of the m6A reader protein YTHDF1 in AML.
• To identify potential therapeutic strategies targeting YTHDF1 in AML.

Main Methods:

• Overexpression of YTHDF1 in human AML samples and leukemia stem cells (LSCs) was assessed.
• YTHDF1's function in AML cell proliferation, self-renewal, and leukemic capacity was evaluated in vitro and in vivo.
• Mechanisms of YTHDF1 action, including its role in cyclin E2 translation, were investigated.
• FDA-approved drugs were screened for YTHDF1 inhibitory activity, leading to the identification of tegaserod.
• Tegaserod's effects on YTHDF1 binding, cyclin E2 translation, AML cell viability, and patient-derived xenograft models were examined.

Main Results:

• YTHDF1 is overexpressed in human AML, particularly in LSCs.
• Depletion of YTHDF1 impairs AML cell self-renewal, proliferation, and leukemic capacity.
• YTHDF1 promotes cyclin E2 translation in an m6A-dependent manner.
• Tegaserod inhibits YTHDF1's interaction with m6A-modified mRNAs and suppresses YTHDF1-driven cyclin E2 translation.
• Tegaserod reduces the viability of patient-derived AML cells and prolongs survival in xenograft models.

Conclusions:

• YTHDF1 is a critical regulator of AML progression by controlling the expression of m6A-modified mRNAs.
• YTHDF1 represents a potential therapeutic target for AML.
• Tegaserod, an FDA-approved drug, demonstrates potential as a YTHDF1 inhibitor for AML treatment.