marrow cells generated by AE
Image courtesy of
The Rockefeller University
Preclinical research has revealed a potential therapeutic target for acute myeloid leukemia (AML)—the histone demethylase JMJD1C.
Investigators found that JMJD1C interacts with RUNX1–RUNX1T1 (formerly AML1-ETO and abbreviated here as AE), a transcription factor generated by the t(8;21) translocation in AML.
However, the team also found that JMJD1C is required for proliferation in many AML cell lines, not just those with AE.
Robert G. Roeder, PhD, of The Rockefeller University in New York, New York, and his colleagues detailed these findings in Genes and Development.
The investigators began this study by searching for proteins that interact with AE, and they identified JMJD1C. To investigate the relationship between JMJD1C and AE, the team explored the broader effects of removing JMJD1C.
“We found that numerous genes were downregulated upon loss of JMJD1C, and the set overlaps significantly with the genes that are normally activated by AE,” said study author Mo Chen, PhD, a researcher in Dr Roeder’s lab.
The investigators also found that AML cells are addicted to the presence of JMJD1C, and, without it, they cannot survive. The team observed an increase in apoptosis when JMJD1C was depleted from Kasumi-1 and SKNO-1 cell lines.
With subsequent experiments, the investigators confirmed that JMJD1C interacts with AE and demonstrated that JMJD1C is required for AE to exert its cancer-promoting effects. But they also found that JMJD1C plays an even broader role in AML.
“We were very surprised to find that JMJD1C is required for the proliferation of other acute myeloid leukemia cell lines, which do not have AE,” Dr Chen said.
The team found that depleting JMJD1C compromised the growth of the following cell lines: Kasumi-1 (AML1-ETO; AML M2), MOLM-13 (MLL-AF9, FLT3ITD; AML M5a), THP-1 (MLL-AF9, NRASmut; AML M5), HNT-34 (BCR-ABL1; AML M4), MV4-11 (MLL-AF4; AML M5), CMK (JAK3A527V; AML M7+ Down’s Syndrome), HEL (AML M6), NOMO-1 (MLL-AF9; AML M5a), NB4 (PML-RARα; AML M3), and HL-60 (MYC amplification; AML M2).
The only cell line that was not affected by depletion of JMJD1C was KG-1 (NRASmut; AML).
To build upon this discovery, the investigators looked for transcription factors aside from AE that might be responsible for JMJD1C addiction. The team found at least 2—LYL1 and HEB—that can recruit JMJD1C to target genes in diseased cells that lack AE, fueling leukemia growth.
The investigators said these results suggest JMJD1C may play a general role in promoting the growth of myeloid leukemias.
“We are excited because this type of general phenomena is an ideal target for drug development,” Dr Roeder said. “Our work will facilitate the development of selective inhibitors against JMJD1C, which is a highly promising therapeutic target for multiple types of leukemia.”
