In the rogue’s gallery of cancer mutations, the Most Wanted are found in TP53, the most frequently mutated gene in cancer and in some ways the most ominous. In patients with acute myeloid leukemia (AML) or a myelodysplastic syndrome (MDS), for example, the presence of a TP53 mutation often means the disease won’t be deterred by chemotherapy and is likely to relapse after a stem cell transplant.

Scientists know the “hot spots” on TP53 where mutations are likely to occur, but research into the effect of those mutations in hematologic cancers has produced mixed results. In a paper in the journal Science, Dana-Farber researchers show that what takes place is a kind of molecular rivalry in which the mutated copy of the gene sabotages the normal, healthy copy — a phenomenon known as the dominant-negative effect.

“We were motivated to explore this issue by the poor prognosis facing patients with these types of myeloid malignancies [which originate in the blood-making tissue of the bone marrow],” says Benjamin Ebert, MD, PhD, chair of the Department of Medical Oncology at Dana-Farber, who led the study with Steffen Boettcher, MD, a postdoctoral fellow in his research laboratory. “By understanding the consequences of TP53 mutations in cancer cells, we may be in a position to devise more effective therapies.”

TP53 is a tumor-suppressor gene, meaning it keeps a cell from growing and dividing recklessly. When TP53 is disabled because of a mutation, a key brake on cancer growth begins to slip. This shutdown of a working gene is known as loss-of-function.

But although TP53 is a tumor-suppressor, it is hardly a typical one. The vast majority of mutations within TP53 occur in hot spots that produce changes in p53, the protein made from the gene. In most other tumor-suppressor genes, however, mutations render the genes inactive, preventing them from generating their protein product.

This oddity led most researchers to hypothesize that the hot spot mutations in TP53 actually create a gain-of-function — that the mutant p53 protein collaborates with other proteins to promote cancer growth. Other researchers saw the dominant-negative effect at work, believing the mutated copy of TP53 undermines the normal copy’s ability to restrain cell division.

To see which, if either, of these explanations is correct, researchers used CRISPR-Cas9 gene-editing technology to create six human leukemia cell lines with the most common TP53 hot spot mutations. Using three different analytic techniques, the investigators found no evidence that the mutations result in a gain-of-function.

Screening the mutant p53 proteins, however, revealed that the proteins wreak their havoc on p53’s function by the dominant-negative effect. The findings were confirmed in animal models and in clinical outcome data from human patients with AML.

“When we undertook this research, we thought it would involve understanding the consequences of gain-of-function of TP53 in myeloid malignancies,” Ebert remarks. “Instead, we found an entirely different process at work. That will be critical in developing therapies for AML and MDS marked by TP53 mutations.”

Dana-Farber co-authors of the study are Peter Miller, MD, PhD; Andrei Krivtsov, PhD; Andrew Giacomelli; Kari Kurppa, PhD; Yael Flamand; Donna Neuberg, ScD; R. Coleman Lindsley, MD, PhD; Pasi A Jänne, MD, PhD; William Hahn, MD, PhD; and Scott Armstrong, MD, PhD.

This article was originally published on September 11, 2019, by Dana-Farber Cancer Institute. It is republished with permission.