Researchers at the Center for Genomic Regulation (CRG) in Barcelona have developed a six-gene scoring system that could help predict survival outcomes in patients with acute myeloid leukemia (AML), an aggressive type of blood cancer. Published in Science Advances, the study identifies a combination of genes whose activity patterns correlate with patient survival and response to treatment. The findings could lay the foundation for more accessible prognostic tests, helping clinicians assess disease outcomes more accurately. To develop the scoring system, the researchers combined laboratory experiments in mice with human patient data to identify genes that showed consistent patterns across both models.
Six Genes Improve Leukemia Prognosis
The researchers identified six genes that collectively predict survival outcomes in patients with AML. Three genes — CARMIL1, HOPX and ALDH1A1 — showed higher activity in patients with poorer outcomes, while CALR, STAR and PHF19 showed lower activity. The team combined the activity levels of these six genes into a scoring system called PHFScore. This score separated patients into groups with significantly different survival prospects. “PHF19 on its own already tells us something about how patients will fare, but combining it with five other genes is a dramatic improvement which gives us more accurate information for AML prognosis,” said ICREA Research Professor Luciano Di Croce, the study’s senior author and a researcher at the CRG. The researchers believe PHFScore could support the development of future prognostic tests. Currently, doctors collect bone marrow samples from patients suspected of having AML for laboratory analysis. Measuring the activity of six genes could offer a simpler and less expensive approach than analysing a broader genetic profile. Furthermore, the study identifies genes that have not previously been linked to blood cancer, opening new avenues for investigating potential therapeutic targets.
PHF19 Offers Clues to Leukemia Development
The study initially focused on PHF19, a gene involved in regulating the activity of other genes. This regulatory system helps cells progress from immature to mature states, a process known as differentiation. Although researchers have generally considered PHF19 to play a role in suppressing blood cancer formation, earlier work from Di Croce’s laboratory revealed that mice lacking this gene develop a condition resembling myelodysplastic syndrome. In this condition, blood cells fail to mature properly and accumulate in the body without necessarily becoming cancerous. The new study investigated how the loss of PHF19 affects blood cells when they acquire an additional genetic change capable of triggering leukemia. “We don’t yet know what they are doing there, which is exactly what makes them worth exploring,” said Dr. Gianni Gamarra, the study’s first author, referring to genes that have not previously been associated with leukemia or blood formation.
Mouse Experiments Reveal More Aggressive Cell Behaviour
To understand PHF19’s role in leukemia, the researchers introduced a leukemia-causing gene into mouse blood cells with and without PHF19. The experiments revealed that cells lacking PHF19 formed more colonies in laboratory conditions and established themselves more readily when transplanted into mice. These cells also remained in an immature, stem-cell-like state rather than progressing towards normal differentiation. According to Gamarra, leukemia develops progressively as cells accumulate defects. Losing PHF19 does not cause leukemia on its own, but it may push cells towards a disease-prone state. The researchers also found that this cellular immaturity could make leukemia harder to treat. Cells without PHF19 largely resisted chemotherapy drugs commonly used to encourage leukemia cells to mature, highlighting a possible connection between gene activity, cellular development and treatment response.
Patient Data Support the Experimental Findings
To establish whether their mouse model reflected human disease, the researchers compared gene activity patterns in mouse cells with data from human AML studies. They found similar molecular patterns in both. Among younger adults treated for AML, patients with the lowest PHF19 activity had shorter survival times than those with the highest activity. They were also less likely to achieve remission following standard chemotherapy. Fewer than half of the patients with the lowest PHF19 levels achieved remission, compared with as many as 85% of those with the highest levels. Although the mouse experiments and human data represented different stages of disease, the similarities in gene activity strengthened the researchers’ confidence in the model.
Six-Gene Score Could Support Future AML Treatment Decisions
The five-year study was led by Di Croce and Gamarra at the CRG, with single-cell analysis expertise from Lars Velten’s group and technical support from the centre’s Genomics Unit and Flow Cytometry Unit. Overall, the findings suggest that PHFScore could help researchers develop more practical tools for predicting AML survival and understanding differences in treatment response. The identification of previously unexplored genes may also provide new directions for studying leukemia biology and potential drug targets. As reported by Medical Xpress, further research and clinical validation will be necessary before the six-gene scoring system can be adopted for routine patient care.