Mapping the cellular origin and early evolution of leukemia in Down syndrome PMID: 34244384

Target-related Cytokines

2026-09-23

Mapping the cellular origin and early evolution of leukemia in Down syndrome

Science. 2021 Jul 9;373(6551):eabf6202. doi: 10.1126/science.abf6202.

Elvin Wagenblast ¹ , Joana Araújo ^# ² ³ ⁴ ⁵ ⁶ , Olga I Gan ^# ² , Sarah K Cutting ² , Alex Murison ² , Gabriela Krivdova ² ⁷ , Maria Azkanaz ² , Jessica L McLeod ² , Sabrina A Smith ² ⁷ , Blaise A Gratton ² , Sajid A Marhon ² , Martino Gabra ⁸ , Jessie J F Medeiros ² ⁷ ⁹ , Sanaz Manteghi ¹⁰ , Jian Chen ¹⁰ , Michelle Chan-Seng-Yue ² ⁹ , Laura Garcia-Prat ² , Leonardo Salmena ² ⁸ , Daniel D De Carvalho ² ¹¹ , Sagi Abelson ⁷ ⁹ , Mohamed Abdelhaleem ¹² , Karen Chong ¹³ ¹⁴ , Maian Roifman ¹³ ¹⁴ , Patrick Shannon ¹⁵ , Jean C Y Wang ² ¹⁶ ¹⁷ , Johann K Hitzler ¹⁰ ¹⁸ ¹⁹ , David Chitayat ¹³ ¹⁴ , John E Dick ¹ ⁷ , Eric R Lechman ¹

Affiliations

1. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. [email protected] [email protected] [email protected].
2. Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
3. Department of Hematology, Centro Hospitalar Universitário de São João, Porto, 4200-319, Portugal.
4. Faculty of Medicine, University of Porto, Porto, 4200-319, Portugal.
5. Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, 4200-135, Portugal.
6. Instituto Nacional de Investigação Biomédica, University of Porto, Porto, 4200-135, Portugal.
7. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
8. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
9. Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
10. Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada.
11. Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada.
12. Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
13. The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5S 1A8, Canada.
14. Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5S 1A8, Canada.
15. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON M5S 1A8, Canada.
16. Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
17. Division of Medical Oncology and Hematology, University Health Network, Toronto, Ontario M5G 2M9, Canada.
18. Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
19. Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
# Contributed equally.

Abstract

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using Gene Editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 (GATA1) mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 MicroRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117⁺/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.