The findings by CRG researchers lay the foundations for new ways of predicting how patients will fare with this type of blood cancer, which has widely variable outcomes from one patient to the next. The team created a scoring system by moving repeatedly between laboratory experiments with mice and patient records, looking for genes that behaved consistently in both.
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."
The researchers say the score could contribute to the development of future prognostic tests. Measuring these six genes is simpler and cheaper than reading a broader genetic profile, a procedure already performed on patients suspected of having AML through bone marrow samples.
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 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 research initially focused on the PHF19 gene, which belongs to a family of genes that keep other genes switched off, a cellular mechanism during the differentiation process from an immature to a mature state. This gene is thought to suppress blood cancer formation.
Earlier work from Luciano Di Croce's lab showed that mice lacking this gene manifested a condition resembling myelodysplastic syndrome, where 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 study investigated what happens when leukaemia originates in cells with similar starting conditions. Researchers introduced a leukaemia-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, remaining in an immature stem-cell-like state.
"Blood cells form a hierarchy," notes 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 plasticity a cancer holds onto, the more malignant it tends to be."
This plasticity made the cells harder to treat. Cells without PHF19 largely ignored the effects of chemotherapeutic drugs, commonly used to push leukaemia cells into a mature state, a medical strategy against the disease where cells get stuck midway through development and multiply unchecked.
To check whether their mouse model reflected human disease, researchers compared which genes were switched on and off in both mouse cells and from data generated in 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. They were also less likely to go into remission after standard chemotherapy, with fewer than half achieving it, compared with up to 85% of patients with the highest levels.
“"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."
The study took five years to complete and was led by Luciano Di Croce and Gianni 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.
