Predicting Leukemia Survival May Be Aided by Six Gene Scoring System

A study by researchers at the Centre for Genomic Regulation (CRG) has identified six different genes that can help forecast survival of patients with acute myeloid leukemia (AML), a type of cancer that has very variable outcomes between patients.

Headed by ICREA Research Professor Luciano Di Croce, PhD, a researcher at the CRG, the team created a 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.

The investigators had initially focused on a gene called PHF19, which the Di Croce lab has studied for more than a decade and is thought to suppress blood cancer formation. PHF19 belongs to a family of genes that keep other genes switched off, a system that cells use as they progress along the differentiation process from immature to mature cells.

Through their research the team found six genes that reliably predict AML 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 called the PHFScore, divided patients into groups with sharply different survival prospects.

Findings from the study could point to new ways of helping to predict outcomes in patients with this type of blood cancer, contributing to the development of future prognostic tests, and may suggest new therapeutic targets. 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.

“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 Di Croce.

Gianni Gamarra Figueroa, PhD, added, “Some of the 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.”

Di Croce is senior author and Gamarra Figueroa is first author of the team’s published paper in Science Advances, titled “Polycomb factor PHF19 affects AML initiation, patient prognosis, and survival.” In their paper the authors concluded “By integrating our in vitro multiomic data with the molecular and clinical data from various AML datasets, we successfully identified a molecular signature—the PHFScore—to identify patient prognosis.”

Acute myeloid leukemia is “… a heterogeneous malignancy characterized by diverse genetic and epigenetic alterations,” the authors wrote.  Earlier work in the Di Croce’s lab showed that mice lacking the PHF19 gene manifest a condition resembling myelodysplastic syndrome (MDS), where blood cells fail to mature properly and build up in the body without yet becoming cancerous. “We previously showed that the Polycomb-associated factor Phf19 is required for hematopoietic stem cell (HSC) maintenance and state control in mice and that its loss (Phf19^KO) impairs HSC function,” the team continued.

“Leukemia develops in stages, as a cell gradually accumulates defects,” explained Gianni Gamarra, PhD, “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,” added Gamarra Figueroa. “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. “Phf19 deletion promoted acquisition of stemlike features and reduced responsiveness to differentiation-inducing AML therapies,” the team stated.

To check whether their mouse model reflected human disease, the researchers compared which genes were switched on and off in both the mouse cells and from data generated in human studies. The same pattern appeared in patient datasets. “Molecular and functional consequences of Phf19 loss paralleled those observed in the datasets of patients with AML,” they further noted. “Patient data from different AML datasets allowed us to determine that patients with low levels of PHF19 expression had a stemlike transcriptomic profile, which, according to the literature, is linked to more chemoresistant leukemias.”

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,” said Gamarra Figueroa.

The post Predicting Leukemia Survival May Be Aided by Six Gene Scoring System appeared first on GEN - Genetic Engineering and Biotechnology News.