YTHDF2's role in promoting acute myeloid leukemia: The key lies in microRNA processing

In a study published in the journal Genes & Diseases, researchers from Beckman Research Institute of City of Hope, explored the impact of m⁶A modification on the maturation process of precursor microRNAs (pre-miRNAs) and its potential role in tumorigenesis. They have uncovered a novel mechanism behind the progression of acute myeloid leukemia (AML), a life-threatening blood cancer characterized by rapid expansion of abnormally differentiated hematopoietic cells.

Despite advances in treatment over the years, the five-year survival rate for AML patients stands at a mere 30%, underscoring the dire need for breakthroughs in understanding and treating this disease. At the heart of this discovery is the RNA m⁶A reader, YTHDF2. This protein, found in elevated levels in AML patients—particularly those who have relapsed, plays a significant role in the disease's progression.

The findings of the research indicate that YTHDF2 accelerates AML by enhancing the expression of a particular microRNA, miR-126-3p (or miR-126). This investigation was particularly centered on the RNA m⁶A reader YTHDF2 and its overexpression in acute myeloid leukemia (AML) patients.

In a significant breakthrough concerning AML, especially in patients who have relapsed, researchers observed a pronounced overexpression of YTHDF2, highlighting its potential oncogenic role. This protein not only amplifies the expression of miR-126-3p, commonly recognized as miR-126, by assisting the maturation of its precursor form, pre-miR-126, but also astutely identifies the m⁶A modification within it. By partnering with AGO2, a pivotal regulator, YTHDF2 facilitates the progression of AML.

Clinically, a direct correlation between YTHDF2's levels and miR-126 has been established, while its relation with miR-126's target genes is inversely proportional. This discovery accentuates miR-126's cardinal role in the YTHDF2 mechanism, where enhancing its expression can potentially offset the impacts of YTHDF2 depletion. This groundbreaking study uncovers a previously unexplored YTHDF2/miR-126 axis in AML progression. By understanding this mechanism, we identify the promising therapeutic potential of targeting this axis for AML treatment. The findings also emphasize m⁶A's influential role in pre-miRNA processing that may contribute to cancer development.

Understanding the intricate roles of m⁶A, YTHDF2, and miR-126 in AML progression offers promising avenues for developing targeted treatments. With miRNAs like miR-126 playing a critical role in AML and other diseases, insights from this study can pave the way for therapies not only for AML but potentially for other conditions impacted by miRNA dysregulation.