Six-gene scoring system could help predict leukemia survival

The activity of six genes can help determine how patients fare with acute myeloid leukaemia (AML), according to a study published today in Science Advances by researchers at the Centre for Genomic Regulation (CRG) in Barcelona. The team built a scoring system, which they call PHFScore, by moving repeatedly between laboratory experiments with mice and human patient records, searching for genes that behaved consistently in both. Some of the six genes, including CARMIL1, HOPX and ALDH1A1, were more active in patients with poor outcomes, while others, including CALR, STAR and PHF19, were less active. When combined, the collective activity of all six genes 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 provide a bone marrow sample for laboratory analysis, and measuring six genes would be simpler and cheaper than reading a broader genetic profile. Some of the genes have never previously been linked to blood cancer. “These genes haven’t been described in leukaemia 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.

The findings grew out of an initial focus on PHF19 alone. The gene 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, and it is generally thought to suppress blood cancer formation. Earlier work in Di Croce’s laboratory, which has studied PHF19 for more than a decade, showed that mice lacking the gene develop a condition resembling myelodysplastic syndrome, in which blood cells fail to mature properly and build up in the body without yet becoming cancerous. “Leukaemia develops in stages, as a cell gradually accumulates defects,” explains Gamarra. “Losing PHF19 doesn’t cause leukaemia on its own, but it is already a push down that road.”

The new study asked what happens when leukaemia originates in cells that start from similar intermediate conditions, not cancerous but not fully healthy either. The researchers introduced a leukaemia-causing gene into mouse blood cells with and without PHF19. Cells lacking the gene formed more colonies in the laboratory and, when transplanted into mice, took hold more easily. They also remained 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.”

That plasticity also made the cells harder to treat. In the mouse experiments, cells without PHF19 largely ignored the effects of chemotherapeutic drugs that are commonly used to push leukaemia 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. These are observations in mouse models and laboratory-grown cells, not demonstrated clinical benefits in patients.

To check whether the mouse model reflected human disease, the researchers compared which genes were switched on and off in the mouse cells and in data generated from human studies. The same pattern appeared in patient datasets. Among younger adults treated for AML, those with the lowest levels of PHF19 survived for less time than those with the highest levels. They were also less likely to go into remission after standard chemotherapy: fewer than half did so, compared with up to 85 percent of patients with the highest PHF19 levels. These figures are associations observed in the studied patient groups rather than predictions for any individual patient, and the six-gene score has not yet been validated as a clinical test.

“The patients have advanced leukaemia, 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 convergence between the mouse model and human datasets is the study’s central methodological strength, but the stage mismatch between the two remains a limitation the authors themselves acknowledge.

The study took five years to complete. It was led by Luciano Di Croce and Gianni Gamarra at the CRG, with single-cell expertise from Lars Velten’s group and support from the CRG’s Genomics Unit and Flow Cytometry Unit. The work lays foundations for new ways of predicting how AML patients will fare with a blood cancer whose outcomes vary widely from one patient to the next, and it identifies genes that could also be explored as potential therapeutic targets, though any such applications remain speculative until the mechanisms of these newly implicated genes are understood.

Subject of Research: A six-gene prognostic score for acute myeloid leukaemia survival based on mouse models and patient data

Article Title: Six-gene scoring system could help predict leukemia survival

Article References: Six-gene scoring system could help predict leukemia survival. Original publication (Bibliographic details unavailable.)

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Keywords: acute myeloid leukaemia, PHF19, PHFScore, gene expression, prognosis, Polycomb, Centre for Genomic Regulation, mouse models, blood cancer, differentiation, chemotherapy resistance, Science Advances