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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 123-138.e10 |
| Journal | Cancer cell |
| Volume | 36 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 12 2019 |
Funding
We thank D. Trono of EPFL, Switzerland for pMD2.G (Addgene plasmid 12259) and psPAX2 (Addgene plasmid 12260). The following funding is acknowledged: J.-H.K. by ERC via European Union Horizon 2020 (no. 714226), DFG (KL-2374/1-3), Beat Leukemia with Connor and St. Baldrick's Robert Arceci Innovations Award; D.H. by German Cancer Aid (111743); D.H. and J.-H.K. by DFG (HE-7482/1-1); M.L. by Hannover Biomedical Research School. P.V. and I.R. by Bloodwise Specialist Programme Grant 13001 and Children with Cancer UK, NIHR Oxford Biomedical Research Fund. P.V. by MRC MHU (MC_UU_12009/11); C.G. by Wellcome Trust Clinical Training Fellowship; L.V. by Mouve-in Louvain and Haas-Teichen Postdoctoral Fellowships; S.C. by WelBio F 44/8/5-MCF/UIG. 10955, Action de Recherche Concert?e 16/21-073, Salus Sanguinis, Foundation ?Les avions de S?bastien,? and Fondation Contre le Cancer, Belgium. M.L. K.P. C.G. R.B. and D.S. performed experiments, analyzed data, and contributed to editing. E.P. S.M. V.A. T.R. V.I. and A.S. analyzed data and contributed to editing. U.O. provided insight into the data and drew a figure. M.-L.Y. and P.J.C. supervised analyses and edited the manuscript. K.Y. J.T. J.D.C. M.J.W. A.H. T.T. E.I. S.O. and D.R. provided patient material and data, and edited the manuscript. L.V. and C.S. performed experiments, analyzed data and edited the manuscript. I.R. S.C. P.V. D.C.H. J.-H.K. designed the study, analyzed the data, wrote the manuscript, and directed the project. D.R. has consulting/advisory roles for Roche, Celgene, Hexal, Pfizer, Novartis, and Boehringer, and receives Celgene research funding. D.R. received travel, accommodation, and expenses from Jazz Pharmaceuticals and Griffols. J.D.C. receives research funding from Scholar Rock and Forma Therapeutics. All other authors declare no competing interests. We thank D. Trono of EPFL, Switzerland for pMD2.G (Addgene plasmid 12259) and psPAX2 (Addgene plasmid 12260). The following funding is acknowledged: J.-H.K. by ERC via European Union Horizon 2020 (no. 714226 ), DFG (KL-2374/1-3), Beat Leukemia with Connor and St. Baldrick's Robert Arceci Innovations Award; D.H. by German Cancer Aid ( 111743 ); D.H. and J.-H.K. by DFG ( HE-7482/1-1 ); M.L. by Hannover Biomedical Research School . P.V. and I.R. by Bloodwise Specialist Programme Grant 13001 and Children with Cancer UK, NIHR Oxford Biomedical Research Fund . P.V. by MRC MHU ( MC_UU_12009/11 ); C.G. by Wellcome Trust Clinical Training Fellowship; L.V. by Mouve-in Louvain and Haas-Teichen Postdoctoral Fellowships; S.C. by WelBio F 44/8/5-MCF/UIG . 10955, Action de Recherche Concertée 16/21-073 , Salus Sanguinis , Foundation “ Les avions de Sébastien ,” and Fondation Contre le Cancer , Belgium. D.R. has consulting/advisory roles for Roche, Celgene, Hexal, Pfizer, Novartis, and Boehringer, and receives Celgene research funding. D.R. received travel, accommodation, and expenses from Jazz Pharmaceuticals and Griffols. J.D.C. receives research funding from Scholar Rock and Forma Therapeutics . All other authors declare no competing interests.
Keywords
- Acute myeloid leukemia
- CRISPR screen
- Down syndrome
- GATA1
- cancer transformation
- preleukemia
ASJC Scopus subject areas
- Oncology
- Cancer Research
