Research News

Cleveland Clinic researchers have identified how mutations in the PHF6 gene influence acute myeloid leukemia (AML), the most common type of leukemia, in male and female patients. The findings shed light on dysregulated blood cell development driving the disease and are linked to poorer prognoses.

PHF6 is a tumor suppressor gene that helps make sure our cells develop and replicate normally. PHF6 mutants are associated with blood cancers, but researchers know very little about how the mutations contribute to disease. This deep-dive study into the intricacies of PHF6 provides researchers and physicians with a vital framework for refining patient risk assessments and customizing treatment strategies based on gender and gene mutations. 

The research is published in Nature Communications and comes from the laboratory of Jaroslaw Maciejewski, MD, PhD, Chair of the Department of Translational Hematology & Oncology Research (THOR) in collaboration with Valeria Visconte, PhD (THOR), and Babal Kant Jha, PhD (THOR and the Center for Immunotherapy & Precision Immuno-Oncology). 

"Until very recently, DNA sequencing experiments focused on generating long lists identifying which genes are mutated during different diseases," explains study first author Yasuo Kubota, MD, PhD, a postdoctoral fellow in Dr. Maciejewski's laboratory. "Modern research requires us to take a deeper, more comprehensive dive into how each gene in the list functions alone, and in the presence of other genes."

Dr. Kubota led a team of researchers and physicians to analyze data from 8,443 patients receiving myeloid neoplasm treatment from Cleveland Clinic, the Munich Leukemia Laboratory and other medical research institutions. The team's investigation into the gene's function used genetic sequencing, epigenetics, gene regulation, protein interactions, clinical outcomes for mutations and more.

The researchers found sex differences in how PHF6 mutants interact with other genes during AML. They saw that PHF6 co-mutated with the genes RUNX1 and U2AF1 in male patients. Female patient data showed that PHF6 co-mutated with different genes entirely. 

"Our findings indicate that physicians should separate risk factors by sex when determining prognoses and treatment plans for specific subgroups of patients," says Dr. Visconte.

The team took their analyses a step further to determine how the different genes interacted with each other and found that the PHF6 protein directly interacts with RUNX1. The two proteins appear to bind to and regulate DNA regions responsible for blood and immune cell development. Because blood and immune cells don't develop correctly during AML, these findings are an important step in understanding how the disease progresses and developing targeted therapies. 

"With the knowledge that different gene mutations can cooperate to cause AML we can design therapies that address multiple genes and molecules involved in cancer progression at once, instead of targeting individual genes," explains study coauthor Xiaorong Gu, PhD. 

Dr. Gu adds that the study's findings can be used in the clinic, as well.

"Working with physicians also lets us get clinical information about PHF6 and see the real-world impact of a single gene mutation," she says. "AML cases with PHF6 mutations had a worse prognosis, especially in association with a mutated RUNX1 gene." 

For AML and other myeloid neoplasms, chemotherapy intensity is often adjusted based on a factor called genetic risk classification, determined by what gene mutations are associated with that patient's case. Dr. Maciejewski's research team identified PHF6 mutations as a high-risk factor for AML, especially in combination with RUNX1 mutations. By further separating the risk classification by sex, Dr. Maciejewski is confident his team's findings can inform treatment plans and improve overall prognosis of AML in the future.