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

Elvin Wagenblast; Joana Araújo; Olga I Gan; Sarah K Cutting; Alex Murison; Gabriela Krivdova; Maria Azkanaz; Jessica L McLeod; Sabrina A Smith; Blaise A Gratton; Sajid A Marhon; Martino Gabra; Jessie J F Medeiros; Sanaz Manteghi; Jian Chen; Michelle Chan-Seng-Yue; Laura Garcia-Prat; Leonardo Salmena; Daniel D De Carvalho; Sagi Abelson; Mohamed Abdelhaleem; Karen Chong; Maian Roifman; Patrick Shannon; Jean C Y Wang; Johann K Hitzler; David Chitayat; John E Dick; Eric R Lechman

doi:10.1126/science.abf6202

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

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

Authors

Elvin Wagenblast¹, Joana Araújo^#^{2

3

4

5

6}, Olga I Gan^#², Sarah K Cutting², Alex Murison², Gabriela Krivdova^{2

7}, Maria Azkanaz², Jessica L McLeod², Sabrina A Smith^{2

7}, Blaise A Gratton², Sajid A Marhon², Martino Gabra⁸, Jessie J F Medeiros^{2

7

9}, Sanaz Manteghi¹⁰, Jian Chen¹⁰, Michelle Chan-Seng-Yue^{2

9}, Laura Garcia-Prat², Leonardo Salmena^{2

8}, Daniel D De Carvalho^{2

11}, Sagi Abelson^{7

9}, Mohamed Abdelhaleem¹², Karen Chong^{13

14}, Maian Roifman^{13

14}, Patrick Shannon¹⁵, Jean C Y Wang^{2

16

17}, Johann K Hitzler^{10

18

19}, David Chitayat^{13

14}, John E Dick^{1

7}, Eric R Lechman¹

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. elvin.wagenblast@uhnresearch.ca john.dick@uhnresearch.ca eric.lechman@uhnresearch.ca.
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.

PMID: 34244384
DOI: 10.1126/science.abf6202

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD34 / analysis
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Cell Lineage
Cell Proliferation
Cell Transformation, Neoplastic
Chromosomal Proteins, Non-Histone / genetics
Chromosomes, Human, Pair 21 / genetics
Chromosomes, Human, Pair 21 / metabolism
Cohesins
Disease Models, Animal
Disease Progression
Down Syndrome / complications
Down Syndrome / genetics*
Female
GATA1 Transcription Factor / genetics*
GATA1 Transcription Factor / metabolism
Hematopoiesis
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / physiology*
Heterografts
Humans
Leukemia, Myeloid / genetics*
Leukemia, Myeloid / metabolism
Leukemia, Myeloid / pathology
Liver / embryology
Male
Megakaryocytes / physiology
Mice
MicroRNAs / genetics
MicroRNAs / metabolism
Mutation
Preleukemia / genetics*
Preleukemia / metabolism
Preleukemia / pathology
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Mas
Proto-Oncogene Proteins c-kit / analysis
Proto-Oncogene Proteins c-kit / antagonists & inhibitors

Substances

Antigens, CD34
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
GATA1 Transcription Factor
GATA1 protein, human
MAS1 protein, human
MicroRNAs
Protein Kinase Inhibitors
Proto-Oncogene Mas
STAG2 protein, human
KIT protein, human
Proto-Oncogene Proteins c-kit