Leukaemia in children, how diseased cells hide for years

A genetic mutation that originates before birth and remains silent for years, allowing potentially cancerous cells to escape the body's controls. This is the mechanism behind childhood leukaemia identified by a group of researchers from the Tettamanti Foundation and the University of Milano-Bicocca, whose findings have been published in the journal Cell Death Discovery. The study sheds new light on the so-called 'pre-leukaemic' phase, a latency period that can last for years before the disease becomes clinically manifest. In this phase, some altered cells manage to survive in the bone marrow without proliferating noticeably, becoming a kind of invisible reservoir from which leukaemia can originate.

At the origin of this phenomenon is an abnormal fusion between two genes, which can occur during foetal development. This alteration produces a protein capable of blocking the growth of cells, but at the same time making them more resistant to normal elimination processes. The result is a biological paradox: the cells do not multiply rapidly, but manage to survive longer than normal, increasing over time the likelihood of accumulating further mutations and turning into cancer cells. "This chromosomal alteration is present in 2-5% of healthy infants, but only a small proportion of carriers actually develop leukaemia before adulthood," explains Denise Acunzo, one of the study's authors. A dynamic that helps explain the long latency phase of the disease. "This study helps us better understand how pre-leukaemic cells manage to survive for years in the bone marrow before the onset of the disease," adds researcher Mayla Bertagna.

One of the most relevant aspects to emerge from the study concerns so-called 'oncogene-induced senescence', a biological state generally considered protective because it blocks cell proliferation. In this case, however, senescence behaves in the opposite way: cells stop dividing but become more resistant to programmed death. In other words, they remain quiescent but difficult to eliminate. This characteristic may explain why leukaemia can appear even years later and why, in some cases, relapses occur after treatment.

Researchers have already started exploring possible strategies to target these 'invisible' cells by testing senolytic drugs that can selectively eliminate senescent cells. Preliminary results indicate that some of these molecules could actually induce the death of pre-leukaemic cells. 'Looking forward, being able to eliminate these cells could help both to reduce the risk of recurrence in patients and, more ambitiously, pave the way for leukaemia prevention strategies,' stresses Giovanni Cazzaniga, Professor of Medical Genetics at the University of Milan-Bicocca and head of the research unit.

In recent years, several international studies have reinforced the idea that childhood leukaemia has a very early origin and can remain silent for a long time. Recent research has confirmed that the ETV6::RUNX1 gene fusion - the same one analysed in the Italia study - can appear as early as prenatally and remain dormant for years, according to the so-called 'two-strike' model: an initial early alteration followed by further mutations leading to full-blown disease. Other work indicates that these pre-leukaemic cells may be more widespread than previously thought: up to 5-6% of healthy newborns would show traces of the mutation, but only a fraction will develop leukaemia, a sign that the initial alteration alone is not sufficient to cause the disease. A key element is precisely the long latency period: clinical studies show that relapses can appear even many years after the initial diagnosis, probably from 'sleeping' cells that were already present from the start. In this context, the contribution of Italian research adds a decisive piece of evidence: it not only confirms the existence of a silent phase, but also clarifies its biological mechanism, explaining how these cells manage to survive over time by escaping the body's control systems.