Researchers identify gene that contributes to secondary cancers

therapy-related myeloid neoplasm
Therapy-related myeloid neoplasm. Image courtesy of the American Society of Hematology.

A 2018 National Institutes of Health study found that patients who received chemotherapy to treat a solid tumor have a small but significant increased risk of developing a secondary cancer later in life that arises from that initial cancer treatment. Known as therapy-related myeloid neoplasms (t-MN), these secondary malignancies are aggressive blood cancers that are difficult to treat. 

Now, a new study by researchers at the University of Chicago Medicine Comprehensive Cancer Center sheds light on how a critical protein, known as CUX1, plays a significant role as a gatekeeper for keeping t-MNs from developing. This research, led by the laboratory of Megan McNerney, MD, PhD, Associate Professor of Pathology, could help scientists develop new methods for treating these secondary cancers, which are expected to increase in incidence as more and more patients survive initial bouts of cancer.

“It's a good thing that patients are surviving long enough to even know about this problem of secondary cancers,” said Molly Imgruet, first author on the study. “But it’s also an unfortunate side effect of chemotherapy that we would like to prevent.”

Researchers initially thought that the chemotherapy itself, because it’s so toxic, was causing the cell mutations that lead to t-MN in some cancer patients. More recently, Imgruet and her co-authors suspected that patients might already be carrying around those mutated cells before treatment and that the chemotherapy somehow triggered a reaction that accelerated the growth of cells that contained a mutation that inactivates the protein-coding gene CUX1. They hypothesized that chemotherapy suppresses normal cells in the bone marrow, yet somehow allows those CUX1-mutated cells to proliferate, eventually causing t-MN. 

To test their theory, they bred CUX1-deficient mice and treated them with chemotherapy, finding that the mice did indeed develop t-MNs. They also investigated why that specific mutation mattered and discovered that CUX1, which is encoded on chromosome 7, appears to regulate what are known as DNA-damage response genes, or DDR genes, which are proteins involved in making the scaffolding to repair DNA damage in cells. 

“So a normal cell gets DNA damage, and it dies,” Imgruet said. “But if it has this CUX1 mutation, it steps on the gas and keeps going anyway. Even if the car is falling apart while you're driving, it keeps going.”

If doctors can identify patients with CUX1 deficiencies before cancer treatment, that information may influence the decision of how to treat such patients.
She and her co-authors note that CUX1 levels decline with age, which may be why older patients are more likely to develop myeloid malignancies such as acute myeloid leukemia. Such patients also often start developing cells that have lost all or part of chromosome 7. The role of chromosome 7, the genes it encodes and how they contribute to the development of blood cancers is an area of intense study, Imgruet said. “It’s possible that the gene EZH2, which is also on chromosome 7, may be working in concert with CUX1,” she said, “and that the cooperation of both of these genes is really important to the loss of chromosome 7.”

Imgruet and her colleagues also found that restoring CUX1 expression prevents myeloid malignancies from developing. That discovery could pave the way for researchers to treat t-MN, perhaps by developing drugs that restore CUX1 function. In the meantime, Imgruet said, if doctors can identify patients with CUX1 deficiencies before cancer treatment, that information may influence the decision of how to treat such patients. 

“If you had someone who had localized breast cancer, and they had the choice to make between either just surgery or surgery plus chemo, then maybe you'd screen them for CUX1 deficiency,” she said. “And you then add that information into the mix when you’re deciding how to treat that patient.” 

The study, “Loss of a 7q gene, CUX1, disrupts epigenetically driven DNA repair and drives therapy-related myeloid neoplasms,” was published on September 2, 2021 in Blood and was supported by the National Cancer Institute (F30 CA232673, R01 CA2311880, R21 CA213247, P30 CA014599, T32 CA009594), the National Heart, Lung and Blood Institute (R01 HL142782), and the National Institute of General Medical Sciences (T32 GM007281). Additional authors include Julian Lutze, Ningfei An, Bonnie Hu, Saira Khan, Jeffrey Kurkewich, Tanner Martinez, Donald Wolfgeher, Sandeep Gurbuxani, and Stephen Kron, all from the University of Chicago.