Six-gene scoring system could help predict leukemia survival
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The activity of six different genes can help determine survival in patients with acute myeloid leukemia (AML), according to a study published in Science Advances. The findings by researchers at the Center for Genomic Regulation (CRG) in Barcelona lay the foundations for new ways of predicting how patients will fare with a type of blood cancer that has widely variable outcomes from one patient to the next.
The team created the scoring system by moving repeatedly between laboratory experiments with mice and patient records, crossing the two to look for genes that behaved consistently in both.
Six genes sharpen survival predictions
They found six genes that reliably predict patient survival. Some genes (CARMIL1, HOPX and ALDH1A1) were more active in patients with poor outcomes, while others (CALR, STAR and PHF19) were less active.
The collective activity of all six genes, which the researchers call PHFScore, divided patients into groups with sharply 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," says ICREA research professor Luciano Di Croce, senior author of the study and researcher at the CRG.
The researchers say the score could contribute to the development of future prognostic tests. Patients suspected of having AML already give a bone marrow sample for laboratory analysis, and measuring six genes is simpler and cheaper than reading a broader genetic profile.
Some of these genes have never been linked to blood cancer before and could also be potential new therapeutic targets. "These genes haven't been described in leukemia or even in how blood forms. We don't yet know what they are doing there, which is exactly what makes them worth exploring," says Dr. Gianni Gamarra, first author of the study.
PHF19 loss leaves cells immature
The findings come from an initial focus on PHF19 alone. It belongs to a family of genes that keep other genes switched off, a system cells use as they progress along the differentiation process from immature to mature cells. It is generally thought to suppress blood cancer formation.
Earlier work in Di Croce's lab, which has studied PHF19 for more than a decade, showed that mice lacking the gene manifest a condition resembling myelodysplastic syndrome, where blood cells fail to mature properly and build up in the body without yet becoming cancerous.
"Leukemia develops in stages, as a cell gradually accumulates defects," explains Gamarra. "Losing PHF19 doesn't cause leukemia on its own, but it is already a push down that road."
The new study asked what happens when leukemia originates in cells that have similar starting conditions—not cancerous, but not quite healthy either. The researchers introduced a leukemia-causing gene into mouse blood cells with and without PHF19. Cells lacking the gene formed more colonies in the lab and, when transplanted into mice, took hold more easily. They also stayed locked in an immature, stem-cell-like state.
"Blood cells form a hierarchy," says Gamarra. "At the top are stem cells, which are still plastic and could become almost anything. As they move down, they mature and take on a fixed identity. The more a cancer holds on to that plasticity, the more malignant it tends to be."
The plasticity made the cells harder to treat. Cells without PHF19 largely ignored the effects of chemotherapeutic drugs which are commonly used to push leukemia cells into a mature state, one of the strategies doctors use against a disease in which cells become stuck partway through development and multiply unchecked.
Patient data echo mouse findings
To check whether their mouse model reflected human disease, the researchers compared which genes were switched on and off in the mouse cells and in data generated in human studies. The same pattern appeared in patient data sets.
Among younger adults treated for AML, those with the lowest levels of PHF19 survived for less time than those with the highest. They were also less likely to go into remission after standard chemotherapy. Fewer than half did so, compared with up to 85% of patients with the highest levels.
"The patients have advanced leukemia, so we are comparing mice and humans at very different stages of the disease, yet the molecular data point in the same direction, which gives our model a great deal of strength," says Gamarra Figueroa.
The study took five years to complete. It was led by Di Croce and Gamarra at the CRG, with single-cell expertise from Lars Velten's group and technological support from the CRG's Genomics Unit and Flow Cytometry Unit.
Publication details
Gianni Paolo Gamarra Figueroa et al., Polycomb Factor Phf19 Affects AML Initiation, Patient Prognosis and Survival, Science Advances (2026). DOI: 10.1126/sciadv.aed6757. www.science.org/doi/10.1126/sciadv.aed6757
Journal information: Science Advances
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