【PNAS】Tsinghua Chen Mo Research Group: Composition mechanism of key transcription complexes of leukemia and new therapeutic targets

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By Jevin

AML1–ETO is the most common fusion transcription factor
in AML.
AE forms a unique and stable transcription factor complex AETFC, which is essential
for the development of leukemia.
Although early studies have shown the biological importance of AETFC components, how AETFC assembly affects gene expression is unclear
.
In addition, the AETFC ingredient LYL1 has been shown to be important
for the proliferation of other types of leukemia.
Therefore, understanding how LYL1 promotes AE-dependent gene expression is important
for the broader leukemia field.
In addition, establishing a correlation between LYL1 and AE-dependent gene activation could guide the discovery
of AETFC coactivators.
The potential for targeted activator-coactivator interactions or enzyme activity may provide new directions
for leukemia treatment.

Despite multiple pieces of evidence of the biological importance of LYL1 in acute myeloid leukemia, how LYL1 co-regulates gene expression with AEs is unclear
.
Researcher Chen Mo's research group at Tsinghua University School of Medicine found that LYL1 plays an important role
in the assembly and transcription activation function of AETFC.
The team's findings were published in Proceedings of the National Academy of Sciences
.

style="box-sizing: border-box;" _msthash="251139" _msttexthash="1839409">Transcription factors and transcription complexes

 01 

Transcription factors (TFs) play a key role in hematopoiesis, and their abnormal expression can lead to various types of leukemia
.
Chromosomal translocation t(8; 21) The resulting fusion protein AML1-ETO (AE) is the most common fusion protein in acute myeloid leukemia, enhancing the self-renewal of leukemia cells and inhibiting the differentiation of bone marrow cells
.
Understanding AE-mediated leukemia is critical to understanding what determines the choice
of AE to activate self-renewal genes or suppress differentiation genes.
That is, although, like many transcription factors, AEs can activate or inhibit target gene expression
.
But it's important
to learn more about how AETFCs assemble and how it regulates gene expression.

LYL1 is a transcription factor containing an alkaline helical spiral domain that binds to DNA with E proteins such as E2A and HEB to form heterodimers and is important
for hematopoietic stem cells/progenitor cells.
LYL1 can also interact directly with the cofactor LMO2 protein to form transcriptional complexes that drive lineage-specific gene expression
in hematopoietic cells and malignancies.

Mechanisms of composition of key transcriptional complexes

 02

Chen Mo's group used biochemical and genomic methods to find that there are at least two different AE-containing complexes in leukemia cells: an AETFC complex containing LYL1 and several AE-E protein complexes without LYL1, and LYL1 plays a key role
in the assembly of AETFC complexes.
Further studies have found that AETFC complexes containing LYL1 preferentially bind to active enhancers and promote activation
of AE target genes.

Next, the researchers further explored the specific mechanisms by
which cofactors specifically bound by the AETFC complex to activate gene transcription.
The researchers identified the cofactors that differentially bind AETFC to AEC by immunoprecipitation-mass spectrometry, and found that the coactivator CARM1 specifically interacts with AETFC and promotes AETFC activation of target genes
.
This study demonstrates that the AETFC complex recruits CARM1 to chromatin, thereby activating target gene expression and promoting AML cell survival, describing the novel role
of the cancer transcription factor LYL1 in AETFC assembly and gene activation.

Research implications

 03 

The above study used biochemical and genomic methods to discover the heterogeneity of AE complex, proved that LYL1 is the key factor in the formation of AETFC complex, and identified for the first time the co-activator CARM1 specifically bound to the complex, which not only provides new insights into the mechanism of AETFC activation target gene transcription, but also provides new targets for the treatment of leukemia
.

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style="white-space: normal;box-sizing: border-box;">Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.