When we think of cancer, we usually imagine a disease that develops over many years in adults. But for one particular group of leukemia – acute lymphoblastic leukemia (ALL) – it is quite the opposite: children are affected more often than adults. An especially aggressive subtype of ALL can even strike infants.
The disease progresses rapidly, sometimes before the age of six months, and responds poorly to treatment. While most children diagnosed with leukemia today have a good chance of recovery, the survival rate for infants with this form is only around 50 percent.
“The big question has long been why infants can develop leukemia so early in life. We know that the critical gene fusion arises already during fetal development, but what in the blood’s maturation process triggers the cancer has been unclear,” says Charlotta Böiers, researcher at Lund University and one of the authors behind the study addressing this question.
When the blood system is most vulnerable
A gene fusion – a genetic alteration where two genes mistakenly fuse together – can occur in both adults, children and fetuses. But it is particularly during fetal life, when the blood system is still forming, that the consequences can be dramatic. It can be compared to a construction site: new blood cells are constantly being produced, and some are more sensitive to disruption.
In infant leukemia, the fusion often occurs between the genes KMT2A and AFF1. This fusion creates an oncogene – a kind of permanently pressed accelerator – that drives cell division and other malignant processes. The Lund researchers have now shown that it is during a sensitive stage of development and in a specific type of fetal blood cell that this oncogene plays a particular role.
Discovery of pre-leukemic stages
When the researchers activated the gene fusion in different blood cells in mice, they discovered a previously unknown expansion of unusual B cells. When the gene was switched on during fetal development, precursor immune cells appeared that expressed the surface protein CD24 – and these early B cells showed characteristics resembling a pre-leukemic state.
“Some cells only exist for a short time during fetal life, and they seem to be particularly susceptible to this genetic change. We believe they may give rise to the pre-leukemic cells,” explains Ariana Calderón, PhD student at Lund University and first author of the study.
Appears only during fetal life
In this delicate phase of blood development, a cell type emerged that did not behave like a normal B cell. It could self-renew and grow abnormally. Moreover, the cells carried a gene expression profile typical of stem cells – including strong expression of the fetal gene HMGA2.
“Together, this suggests that these particular cells may represent the very first building block in the disease process. This cell population does not appear in adults – only when we activate the gene fusion during fetal development,” says Ariana Calderón.
It provides a piece of the puzzle to the answer of why leukemia can occur so early in infants.
When the researchers compared their findings with patient data from international cohorts, they found similar gene expression patterns in infants with aggressive ALL.
“It gives us valuable confirmation that our model is relevant to human disease – and indicates that these precursor cells might persist into the developed leukemia. That’s something we aim to explore further,” says Calderón.
Significance for the future
Although the study is basic research, it provides important clues.
CD24 is being evaluated as a potential new target for cancer immunotherapies. HMGA2 may also be of interest – when this gene was turned off in lab experiments, the leukemia cells’ growth decreased, explains Charlotta Böiers.
The next step for the researchers is to investigate even earlier stages of blood development – perhaps the first blood cells that arise in the yolk sac and aorta.
“Knowledge is the first step, even if treatment is still far away. If we can pinpoint when and where in fetal development the disease begins, we can start thinking about how to stop it,” says Charlotta Böiers.