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How leukemia develops in children with Down syndrome – molecular steps now traced for the first time by a research team led by Prof. Jan-Henning Klusmann, LOEWE-FCI and intern. colleagues
Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia (ML-DS). This is because 15 to 30 percent of newborns with Down syndrome experience a temporary disorder of the blood-forming system called transient abnormal myelopoiesis (TAM). In the acute phase, TAM is virtually indistinguishable from ML-DS: In both cases, the precursor cells of white blood cells, or leukocytes, proliferate uncontrollably in the bone marrow. This displaces normal blood-forming cells, which can lead to anemia, impaired immune function, and an increased tendency to bleed. Unlike ML-DS, TAM is reversible. Because the two diseases are so similar, TAM patients often receive cancer treatment as well.
A research team led by Prof. Jan-Henning Klusmann of Goethe University Frankfurt, Prof. Jack Bartram of Great Ormond Street Hospital in London, and Prof. Sam Behjati of the Wellcome Sanger Institute in Hinxton, UK, has now traced the individual molecular steps of cancer development for the first time.
To do this, the research team examined tumor samples from young patients suffering from TAM or ML-DS in various forms and stages. The scientists used a method that identifies which genes are active in individual TAM or cancer cells, known as single-cell mRNA sequencing. They also scanned the genome of these cells for mutations, focusing particularly on the GATA1 protein, a mutation of which triggers TAM. This is a type of switch protein (transcription factor) that orchestrates the normal development of blood cells, and its malfunction in TAM and ML-DS cells contributes to rapid and uncontrolled growth.
The result: While different genes contributing to the disease are active depending on the developmental stage of TAM and ML-DS cells, and different mutations are responsible for varying degrees of severity or stages of the two diseases, the gene activities attributable to the mutation in GATA1 were similar in all TAM and ML-DS cells.
The results show that different genes are active depending on the developmental stage of TAM and ML-DS cells. However, different mutations are responsible for different degrees of severity or stages of the two diseases. Prof. Jan-Henning Klusmann, scientist at the LOEWE Center FCI and co-senior author at Goethe University Frankfurt, said: “We have known for some time that children with Down syndrome have an increased risk of myeloid leukemia. Now we have deciphered the underlying genetic programs and – initially in the laboratory – discovered which cells of the TAM precursor can develop into myeloid leukemia in children with Down syndrome.”
Original publication: Mi K. Trinh, Konstantin Schuschel, Hasan Issa, Rebecca Thomas, Conor Parks, Agnes Oszlanczi, Toochi Ogbonnah, Di Zhou, Lira Mamanova, Elena Prigmore, Emilia Robertson, Angus Hodder, Anna Wenger, Nathaniel D. Anderson, Holly J. Whitfield, Taryn D. Treger, José Gonçalves-Dias, Karin Straathof, David O'Connor, Matthew D. Young, Laura Jardine, Stuart Adams, Jan-Henning Klusmann, Jack Bartram, Sam Behjati: Single cell transcriptional evolution of myeloid leukaemia of Down syndrome. Nature Communications (2026), https://doi.org/10.1038/s41467-026-71707-2