Fusion Gene Coactivator Is Critical for Acute Myeloid Leukemia Growth

Researchers are beginning to unravel the tangled web of molecular pathways that promote the development and progression of the bone marrow cancer acute myeloid leukemia (AML).

AML is an aggressive cancer that strikes both adults and children and is frequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical step toward developing new approaches for treating this disease.

Investigators at the Rockefeller University (New York, NY, USA) focused their attention on a DNA rearrangement that is found in about 15% of AML patients. This rearrangement results in the fusion gene RUNX1–RUNX1T1 (formerly AML1-ETO) that produces a mutant protein called AE.

Runt-related transcription factor 1 (RUNX1), also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2), is a transcription factor that regulates the differentiation of hematopoietic stem cells into mature blood cells. It belongs to the Runt-related transcription factor (RUNX) family of genes which are also called core binding factor-alpha (CBFalpha). Chromosomal translocations involving the RUNX1 gene are associated with several types of leukemia including M2 AML.

The protein encoded by the RUNX1T1 gene is a putative zinc finger transcription factor and oncoprotein. In acute myeloid leukemia, especially in the M2 subtype, the t(8;21)(q22;q22) translocation is one of the most frequent karyotypic abnormalities. The translocation produces a chimeric gene made up of the 5'-region of the RUNX1 gene fused to the 3'-region of the RUNX1T1 gene. The chimeric protein is thought to associate with the nuclear corepressor/histone deacetylase complex to block hematopoietic differentiation.

The investigators reported in the October 21, 2015, online edition of the journal Genes and Development that the histone demethylase enzyme JMJD1C (jumonji domain containing 1C), functioned as a coactivator for RUNX1–RUNX1T1 and was required for its transcriptional program. JMJD1C was directly recruited by RUNX1–RUNX1T1 to its target genes and regulated their expression by maintaining low levels of the histone H3K9 dimethyl (H3K9me2).

Analyses conducted in a model system comprising mice that had been genetically engineered to lack the JMJD1C gene also established a JMJD1C requirement for RUNX1–RUNX1T1's ability to increase AML proliferation.

The investigators also identified a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it was required for leukemic programs in different AML cell types through its association with key transcription factors.

"These results suggest that JMJD1C may play a general role in promoting growth in myeloid leukemias," said senior author Dr. Robert G. Roeder, professor of biochemistry and molecular biology at the Rockefeller University. "We are excited because this type of general phenomena is an ideal target for drug development. Our work will facilitate the development of selective inhibitors against JMJD1C, which is a highly promising therapeutic target for multiple types of leukemia."

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