Study Identifies New Treatment Option for Severe Leukemia Patients

Recent advancements have found a novel approach to treating Acute Myeloid Leukemia (AML), the most common form of leukemia. These findings come from a group of researchers at the Vetmeduni Vienna and the Ludwig Boltzmann Institute for Cancer Research, who found that activity of the mutated oncogene C/EBPα is dependent on a specific epigenetic factor. This factor, MLL1 histone methyltransferase complex, was found to be linked to death of AML cells with C/EBPα mutations.

According to the study results, published in Leukemia, an interaction between the mutated protein and this epigenetic regulator leads to vulnerability of these AML cells. If the MLL1 complex was inhibited, the researchers noted that the AML cells went through cell death. By targeting MLL1 with inhibitory drugs, the block in blood cell maturation caused by the cancer could be potentially alleviated in AML patients.

The transcription factor CCAAT/enhancer binding protein alpha C/EBPα is an important regulatory factor of blood development that controls critical functions in blood maturation. In 10-15% of AML patients, however, the C/EBPα gene contains mutations that prevent proper formation of the correct protein.

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“In AML patients, most mutations occur in the N-terminal part of the CEBPA gene. This leads to the production of a shortened C/EBPα protein, the isoform p30, which is responsible for keeping cells in an immature state and can thus trigger leukemia,” said study author Luisa Schmidt.

The over-produced C/EBPα p30 protein variant uses epigenetic mechanisms to control gene expression in leukemia cells. This specific protein isoform has been associated with genetic expression patterns seen in leukemia cells. The variant binds promoters of oncogenes and recruits chromatin-modifying complexes such as histone methyltransferases. The MLL1 complex is one of these specific complexes required for transcriptional activation and is critical for hematopoietic stem cell maintenance as well.

“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,” said Schmidt.

Studies of protein-DNA interactions have shown that the C/EBPα p30 isoform binding pattern strongly overlaps with MLL1’s, suggesting that the two factors interact with one another. This hypothesis was supported in additional experimenting.

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Targeting the MLL1 complex with CRISPR/Cas9 mutagenesis further demonstrated C/EBPα-mutated AML cell growth being dependent on correct functioning of the MLL1 complex. Such AML cells were observed to be highly sensitive to pharmacological inhibition of MLL1 complexes. Inhibiting the complex was associated with impaired cell proliferation and death of the mutated AML cells. This treatment was also associated with reversal of the differentiation block of cancer cells, restoring normal blood cell maturation.

“The result that C/EBPα p30 requires a functional MLL1 complex to control oncogenic gene expression programs reveals a high sensitivity of CEBPA- mutated AML to the inhibition of the MLL1 complex function,” said study leader Florian Grebien. “These results broaden our understanding of CEBPA-mutated AML and identify the MLL1 complex as a potential therapeutic target for this disease.”

Source: Science Daily