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Thursday, November 7, 2019

Why Some Forms of Leukemia Only Affect Children

Acute myeloid leukemia (AML) mainly affects children, with the prognosis often being poor despite several decades of research into more effective treatments. A new study led by Thomas Mercher, PhD, (Inserm U1170/Gustave Roussy/Université Paris-Sud-Paris Saclay), and performed in collaboration with Jürg Schwaller, MD, (UKBB, Department of Biomedicine, Universität Basel), explains why some forms of leukemia develop in very young children. The study—published in Cancer Discovery—has also revealed potential new therapeutic targets. (2019; doi: 10.1158/2159-8290.CD-18-1463).

Over recent decades, research into pediatric cancer has intensified and treatments have improved, but the prognosis remains particularly unfavorable for these young patients. Acute myeloid leukemia (AML) accounts for 15 percent of cases of leukemia diagnosed in children and adolescents. Overall survival at 5 years is around 60 percent, with relapse being the most common cause of mortality.

Through the CONECT-AML collaborative network in France, the scientists obtained samples from young patients with AML-M7. In 2012, their analysis of these samples had already revealed AML-M7 to frequently present genetic alterations that lead to the expression of an abnormal protein resulting from the fusion of the two proteins normally independent in the cell. At that time, although this fusion—known as ETO2-GLIS2—had been identified in 30 percent of AML-M7 cases, the researchers could not explain its mechanism of action.

"One of the objectives of our new study was to look at the mechanism of action of the ETO2-GLIS2 fusion, and to better elucidate its consequences. We wanted to answer two major questions, with the first being why this disease is specific to children—since the fusion is not found in adults, and then what the potential therapeutic avenues could be." explained Thomas Mercher.

This involved the researchers analyzing the characteristics of human leukemia cells and developing a mouse model to study the consequences of the ETO2-GLIS2 fusion.

In this model, the researchers showed that this fusion is sufficient in order to rapidly induce aggressive leukemia, if it is activated in fetal hematopoietic cells. However, there is little to link its activation in adult cells with the development of leukemia. Moreover, blocking the ETO2-GLIS2 fusion in the in vivo model brings tumor proliferation to a halt, with the abnormal blood cells once again able to differentiate into normal blood cells.

These findings make it possible to propose new target mechanisms in fetal cells and pediatric leukemia in order to improve treatments for these patients. "We now want to understand exactly how this fusion works. Targeting it in order to directly inhibit it with molecules that could be used in patients is not something we are able to do at present, so instead we will identify and try to target the surrounding proteins that are important for it to function", Mercher concluded.