Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome PMID: 31303423

ADC Targets in Oncology

2026-04-10

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome

Cancer Cell. 2019 Aug 12;36(2):123-138.e10. doi: 10.1016/j.ccell.2019.06.007.

Maurice Labuhn ¹ , Kelly Perkins ² , Sören Matzk ³ , Leila Varghese ⁴ , Catherine Garnett ² , Elli Papaemmanuil ⁵ , Marlen Metzner ² , Alison Kennedy ² , Vyacheslav Amstislavskiy ⁶ , Thomas Risch ⁶ , Raj Bhayadia ⁷ , David Samulowski ⁷ , David Cruz Hernandez ² , Bilyana Stoilova ² , Valentina Iotchkova ² , Udo Oppermann ⁸ , Carina Scheer ¹ , Kenichi Yoshida ⁹ , Adrian Schwarzer ¹ , Jeffrey W Taub ¹⁰ , John D Crispino ¹¹ , Mitchell J Weiss ¹² , Yasuhide Hayashi ¹³ , Takashi Taga ¹⁴ , Etsuro Ito ¹⁵ , Seishi Ogawa ¹⁶ , Dirk Reinhardt ¹⁷ , Marie-Laure Yaspo ⁶ , Peter J Campbell ¹⁸ , Irene Roberts ¹⁹ , Stefan N Constantinescu ⁴ , Paresh Vyas ²⁰ , Dirk Heckl ²¹ , Jan-Henning Klusmann ²²

Affiliations

1. Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
2. MRC MHU, BRC Hematology Theme, Oxford Biomedical Research Centre, Oxford Centre for Haematology, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
3. Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
4. Ludwig Institute for Cancer Research Brussels Branch, 1200 Brussels, Belgium.
5. Departments of Epidemiology and Biostatistics and Cancer Biology, MSKCC, New York, NY 10065, USA.
6. Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
7. Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany.
8. Botnar Research Centre, NDORMS, Oxford NIHR BRC and Structural Genomics Consortium, UK University of Oxford, Oxford OX3 7LD, UK.
9. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8315 Japan.
10. Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI 48201, USA.
11. Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA.
12. Hematology Department, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
13. Institute of Physiology and Medicine, Jobu University, Takasaki-shi, Gunma 370-0033, Japan.
14. Department of Pediatrics, Shiga University of Medical Science, Shiga 520-2192, Japan.
15. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
16. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8315 Japan; Center for Hematology and Regenerative Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.
17. Pediatric Hematology and Oncology, Pediatrics III, University Hospital Essen, 45122 Essen, Germany.
18. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
19. MRC MHU, BRC Hematology Theme, Oxford Biomedical Research Centre, Oxford Centre for Haematology, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Paediatrics, University of Oxford, Oxford OX3 9DS, UK.
20. MRC MHU, BRC Hematology Theme, Oxford Biomedical Research Centre, Oxford Centre for Haematology, WIMM, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; Department of Haematology, Oxford University Hospitals NHS Trust, Oxford OX3 7LE, UK. Electronic address: [email protected].
21. Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany; Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. Electronic address: [email protected].
22. Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany. Electronic address: [email protected].

Abstract

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.

Keywords

Acute myeloid leukemia; CRISPR screen; Down syndrome; GATA1; cancer transformation; preleukemia.