Researchers at Children’s Hospital of Philadelphia (CHOP) are shedding light on how two genetic factors – an extra copy of chromosome 21 (trisomy 21) and mutations in the GATA1 gene – interact to derail early blood cell development. These changes are linked to certain blood disorders seen in patients with Down syndrome, particularly in a condition called transient abnormal myelopoiesis (TAM) and a type of leukemia called myeloid leukemia associated with Down syndrome (ML-DS). The research, published recently in the journal Stem Cell Reports, looks at the precise way these genetic abnormalities work together to influence cell behavior.
Patients with Down syndrome often experience abnormal blood cell patterns that begin early in life. These can include high red blood cell counts at birth, low platelet levels and a significantly increased risk of developing leukemia. GATA1 mutations that occur in individuals without trisomy 21 tend to cause a congenital anemia without increasing the risk of leukemia. This suggests that both trisomy 21 and GATA1 mutations are necessary to cause TAM and ML-DS, and researchers sought to better understand what happens when these two genetic factors occur together.
In the study, researchers used advanced stem cell and single-cell RNA sequencing techniques to engineer human stem cells into four groups: one with only the extra chromosome 21, one with only the GATA1 mutation, one with both and a control group with neither. The researchers then analyzed thousands of individual blood-forming cells to see which genes were active in each one – essentially creating a high-resolution map of how each genetic scenario affected blood development.
They discovered that each genetic factor on its own altered blood development in a distinct way, which helps researchers understand how individual genetic abnormalities affect blood cell development and helps pinpoint the mechanisms behind blood disorders. For example, the GATA1 mutation nearly wiped out production of red blood cells, slowing down the maturation of platelet-producing cells and producing more white blood cells. On the other hand, the extra chromosome 21 increased red blood cell production but negatively affected platelet production.
When both factors were present, the effects became more complex and prone to malfunctioning. The extra chromosome appeared to try to boost red blood cell formation, but the GATA1 mutation blocked the process, resulting in a build-up of immature red blood and platelet precursor cells. Meanwhile, the shift toward white blood cell production continued. The result was a proliferation of cells stuck in an immature state – an environment conducive to the development of leukemia.
“Our findings help paint a picture of how two genetic alterations in Down syndrome interact to set the stage for blood cancers,” said Kaoru Takasaki, MD, the lead study author and an attending physician with the Division of Hematology at Children’s Hospital of Philadelphia. “We hope these insights will catalyze further research aimed at improving screening protocols and advancing targeted treatment for at-risk children.”
This work was supported by NIH (R01 HL151260) and (R01 DK090969), (T32 HL0007150), and (K99 HL56052), the Hyundai Hope on Wheels Foundation, a Distinguished Chair in Pediatrics, the American Society of Hematology Research Training Award for Fellows, the Doris Duke Charitable Foundation Physician Scientist Fellowship and the Ken Mizuno Fund in Hematology.
Takasaki et al. “Single-cell transcriptomics reveal individual and cooperative effects of Trisomy 21 and GATA1s on hematopoiesis”. Stem Cell Reports. Online July 17, 2025. DOI: 10.1016/j.stemcr.2025.102577.
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Researchers at Children’s Hospital of Philadelphia (CHOP) are shedding light on how two genetic factors – an extra copy of chromosome 21 (trisomy 21) and mutations in the GATA1 gene – interact to derail early blood cell development. These changes are linked to certain blood disorders seen in patients with Down syndrome, particularly in a condition called transient abnormal myelopoiesis (TAM) and a type of leukemia called myeloid leukemia associated with Down syndrome (ML-DS). The research, published recently in the journal Stem Cell Reports, looks at the precise way these genetic abnormalities work together to influence cell behavior.
Patients with Down syndrome often experience abnormal blood cell patterns that begin early in life. These can include high red blood cell counts at birth, low platelet levels and a significantly increased risk of developing leukemia. GATA1 mutations that occur in individuals without trisomy 21 tend to cause a congenital anemia without increasing the risk of leukemia. This suggests that both trisomy 21 and GATA1 mutations are necessary to cause TAM and ML-DS, and researchers sought to better understand what happens when these two genetic factors occur together.
In the study, researchers used advanced stem cell and single-cell RNA sequencing techniques to engineer human stem cells into four groups: one with only the extra chromosome 21, one with only the GATA1 mutation, one with both and a control group with neither. The researchers then analyzed thousands of individual blood-forming cells to see which genes were active in each one – essentially creating a high-resolution map of how each genetic scenario affected blood development.
They discovered that each genetic factor on its own altered blood development in a distinct way, which helps researchers understand how individual genetic abnormalities affect blood cell development and helps pinpoint the mechanisms behind blood disorders. For example, the GATA1 mutation nearly wiped out production of red blood cells, slowing down the maturation of platelet-producing cells and producing more white blood cells. On the other hand, the extra chromosome 21 increased red blood cell production but negatively affected platelet production.
When both factors were present, the effects became more complex and prone to malfunctioning. The extra chromosome appeared to try to boost red blood cell formation, but the GATA1 mutation blocked the process, resulting in a build-up of immature red blood and platelet precursor cells. Meanwhile, the shift toward white blood cell production continued. The result was a proliferation of cells stuck in an immature state – an environment conducive to the development of leukemia.
“Our findings help paint a picture of how two genetic alterations in Down syndrome interact to set the stage for blood cancers,” said Kaoru Takasaki, MD, the lead study author and an attending physician with the Division of Hematology at Children’s Hospital of Philadelphia. “We hope these insights will catalyze further research aimed at improving screening protocols and advancing targeted treatment for at-risk children.”
This work was supported by NIH (R01 HL151260) and (R01 DK090969), (T32 HL0007150), and (K99 HL56052), the Hyundai Hope on Wheels Foundation, a Distinguished Chair in Pediatrics, the American Society of Hematology Research Training Award for Fellows, the Doris Duke Charitable Foundation Physician Scientist Fellowship and the Ken Mizuno Fund in Hematology.
Takasaki et al. “Single-cell transcriptomics reveal individual and cooperative effects of Trisomy 21 and GATA1s on hematopoiesis”. Stem Cell Reports. Online July 17, 2025. DOI: 10.1016/j.stemcr.2025.102577.
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