Abstract
Loss of the m6A reader YTHDF2 compromises leukemic stem-cell activity while promoting normal HSC expansion.
Major Finding: Loss of the m6A reader YTHDF2 compromises leukemic stem-cell activity while promoting normal HSC expansion.
Mechanism: YTHDF2 decreases the half-life of m6A-modified mRNAs that limit LSC activity and leukemogenic potential.
Impact: YTHDF2 may be therapeutic target in AML whose inhibition would also be advantageous to normal HSCs.
The YTH domain proteins are the functional “readers” of the mRNA N6-methyladenosine (m6A) modification, which regulates mRNA processing, translation, and degradation. A host of m6A-dependent processes regulate hematopoietic stem cell (HSC) biology and acute myeloid leukemia (AML) pathogenesis, and this pathway represents an attractive avenue for therapeutic intervention. Paris and colleagues sought to determine the effect of YTHDF2, which mediates the degradation of m6A-modified transcripts, on AML pathogenesis and maintenance. Profiling YTHDF2 expression in primary AML patient samples revealed that YTHDF2 expression is significantly upregulated across all clinical AML subtypes. Furthermore, YTHDF2 expression was significantly enriched in the CD34+ primitive cell compartment of AML samples. Ythdf2 deletion in a Meis1–Hoxa9-driven mouse AML model decreased the clonogenic capacity of progenitor cells and overall leukemic stem cell (LSC) frequency, which corresponded to a longer disease latency period. This was borne out in additional AML models driven by other oncogenic fusions. YTHDF2 knockdown in primary human AML samples also decreased their proliferative capacity. However, Ythdf2 deletion in normal HSCs actually promoted their expansion and increased myeloid cell reconstitution in competitive repopulation assays. Detailed transcriptome profiling of Ythdf2 knockout LSCs revealed that YTHDF2 regulates the half-life of m6A-modified transcripts and that transcripts negatively correlated with YTHDF2 expression were highly associated with the loss of leukemogenic potential. Collectively, this work demonstrates that YTHDF2 inhibition compromises AML propagation by regulating the stability of transcripts necessary for LSC maintenance while enhancing normal HSC function, underscoring the therapeutic potential of targeting YTHDF2 activity in AML.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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