[ICKSH 2025] ‘Advancing genetic insights to refine treatment strategies for Down syndrome-associated myeloid leukemia’

Myeloid leukemia associated with Down syndrome (ML-DS) is a unique subtype of acute myeloid leukemia (AML) occurring predominantly in children with Down syndrome.

Notably, children with ML-DS generally exhibit a favorable prognosis, with event-free survival rates approaching 90 percent. This improved outcome is largely attributed to the heightened sensitivity of ML-DS blasts to chemotherapy agents, particularly cytarabine.

At the recent International Conference of the Korean Society of Hematology (ICKSH) 2025, Professor Etsuro Ito of Hirosaki University Graduate School of Medicine in Japan presented a comprehensive update titled “Advances in the Genetics of Down Syndrome-Related Myeloid Leukemia.”

His lecture provided a detailed look into the molecular heterogeneity of ML-DS and its clinical implications.

Based on an extensive genomic analysis of 204 pediatric ML-DS patients, Professor Ito’s team identified a range of recurrent and novel driver mutations, including IRX1, ZBTB7A, and RUNX1-PTD.

Ito highlighted that alterations in genes such as CDKN2A, TP53, ZBTB7A, and JAK2 were significantly associated with inferior three-year event-free survival (EFS), presenting new markers for risk stratification.

“Our data suggest that genetic profiling of ML-DS at diagnosis could help predict prognosis more accurately and guide treatment intensity,” Ito said. “Particularly, mutations in genes like TP53 or JAK2 may flag patients who require closer monitoring or future inclusion in trials for targeted therapies.”

A focal point of his presentation was the functional significance of IRX1, a gene newly implicated in ML-DS leukemogenesis.

Professor Ito's group demonstrated that IRX1 expression interferes with normal megakaryocytic differentiation, pointing to disrupted hematopoietic lineage commitment as a hallmark of ML-DS pathophysiology.

“IRX1 not only emerged as a frequent driver mutation, but also showed biological activity that could make it a potential therapeutic target,” Ito said.

RNA sequencing and gene set enrichment analyses confirmed that IRX1 participates in several differentiation and signaling pathways crucial to leukemia progression.

Notably, Professor Ito drew attention to the transition from transient abnormal myelopoiesis (TAM)—a self-limiting myeloproliferative condition found in 5–10 percent of neonates with Down syndrome—to full-blown ML-DS, which occurs in roughly 20 percent of those cases.

“By elucidating the genetic mechanisms that drive progression from TAM to ML-DS, we aim to better understand which patients are at risk and how to intervene earlier,” he said. “This knowledge could eventually lead to preventive strategies or pre-emptive treatments.”

Professor Ito concluded his session by stressing that the future of ML-DS treatment will depend on how well physicians integrate genetic information into clinical decision-making.

“These data are not just for academic interest—they are the foundation of tomorrow’s personalized therapies,” he said.