Researchers Identify New Therapeutic Strategy for AML

Acute myeloid leukemia (AML) is characterized by an increase of malignant myeloid progenitor cells at the expense of mature blood cells.

Researchers at the Ludwig Boltzmann Institute for Cancer Research and the VetMedUni (Vienna, Austria) have identified a new potential therapy for the treatment of AML patients, which carry a mutated, oncogenic isoform of the protein C/EBPα.  

The transcription factor CCAAT/enhancer binding protein alpha C/EBPα plays a significant role in regulating blood development, controlling critical steps in the maturation of blood cells. However, in 10% to 15% percent of AML patients, the CEBPA gene contains mutations that prevent the formation of the correct protein isoform.

Epigenetic processes can control the expression of genes, and the C/EBPα p30 isoform uses these processes to regulate gene expression patterns of leukemia cells. This oncogenic variant binds to the promoters of certain genes and recruits chromatin-modifying complexes, including histone methyltransferases. One of these interaction partners is the MLL1 complex, which is required for transcriptional activation and has been shown to be critical for the maintenance of hematopoietic stem and progenitor cells.

In the present study, researchers found that the interaction of the mutated protein with an epigenetic regulator, the so-called MLL1 complex, represents a specific vulnerability of AML cells with CEBPA mutations. If the MLL1 complex was functionally inhibited, AML cells underwent cell death. Via targeted inhibition of MLL1, the cancer-associated block in normal blood cell maturation could potentially be released in affected AML patients.

First-author Luisa Schmidt (Ludwig Boltzmann Institute) said that “Using a combination of biochemical, genetic and pharmacological approaches, we have now been able to show that the MLL1 histone methyltransferase complex is a critical vulnerability in AML with CEBPA mutations” (Science Daily. 2019 Feb 13. Epub ahead of print).

Moreover, targeting of the MLL1 complex function by CRISPR/Cas9-mediated mutagenesis of the MLL1 protein demonstrated that the growth of AML cells with CEBPA mutations depends on the correct assembly and chromatin anchoring of the MLL1 complex. AML cells with CEBPA mutations were highly sensitive to pharmacological inhibition of the MLL1 complex by specific small-molecule inhibitors. MLL1 complex inhibition impaired proliferation and caused death of AML cells with CEBPA mutations. Treatment of CEBPA-mutated AML cells with MLL1 complex inhibitors reversed the differentiation block of cancer cells and restored normal maturation of blood cells.

Authors posited that study results “broaden our understanding of CEBPA-mutated AML and identify the MLL1 complex as a potential therapeutic target for this disease.”

Full study and results were published in Leukemia (doi:10.1038/s41375-019-0382-3).—Amanda Del Signore