Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome
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 r...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2019
|
| _version_ | 1797099804328722432 |
|---|---|
| author | Labuhn, M Perkins, K Matzk, S Varghese, L Garnett, C Papaemmanuil, E Metzner, M Kennedy, A Amstislavskiy, V Risch, T Bhayadia, R Samulowski, D Hernandez, D Stoilova, B Iotchkova, V Oppermann, U Scheer, C Yoshida, K Schwarzer, A Taub, J Crispino, J Weiss, M Hayashi, A Taga, T Ito, E Ogawa, S Reinhardt, D Yaspo, M Campbell, P Roberts, I Constantinescu, S Vyas, P Heckl, D Klusmann, J |
| author_facet | Labuhn, M Perkins, K Matzk, S Varghese, L Garnett, C Papaemmanuil, E Metzner, M Kennedy, A Amstislavskiy, V Risch, T Bhayadia, R Samulowski, D Hernandez, D Stoilova, B Iotchkova, V Oppermann, U Scheer, C Yoshida, K Schwarzer, A Taub, J Crispino, J Weiss, M Hayashi, A Taga, T Ito, E Ogawa, S Reinhardt, D Yaspo, M Campbell, P Roberts, I Constantinescu, S Vyas, P Heckl, D Klusmann, J |
| author_sort | Labuhn, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T05:28:48Z |
| format | Journal article |
| id | oxford-uuid:e17cd56b-7903-489b-bf90-a1c8a2092d4c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:28:48Z |
| publishDate | 2019 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:e17cd56b-7903-489b-bf90-a1c8a2092d4c2022-03-27T09:54:58ZMechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndromeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e17cd56b-7903-489b-bf90-a1c8a2092d4cEnglishSymplectic Elements at OxfordElsevier2019Labuhn, MPerkins, KMatzk, SVarghese, LGarnett, CPapaemmanuil, EMetzner, MKennedy, AAmstislavskiy, VRisch, TBhayadia, RSamulowski, DHernandez, DStoilova, BIotchkova, VOppermann, UScheer, CYoshida, KSchwarzer, ATaub, JCrispino, JWeiss, MHayashi, ATaga, TIto, EOgawa, SReinhardt, DYaspo, MCampbell, PRoberts, IConstantinescu, SVyas, PHeckl, DKlusmann, JMyeloid 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. |
| spellingShingle | Labuhn, M Perkins, K Matzk, S Varghese, L Garnett, C Papaemmanuil, E Metzner, M Kennedy, A Amstislavskiy, V Risch, T Bhayadia, R Samulowski, D Hernandez, D Stoilova, B Iotchkova, V Oppermann, U Scheer, C Yoshida, K Schwarzer, A Taub, J Crispino, J Weiss, M Hayashi, A Taga, T Ito, E Ogawa, S Reinhardt, D Yaspo, M Campbell, P Roberts, I Constantinescu, S Vyas, P Heckl, D Klusmann, J Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome |
| title | Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome |
| title_full | Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome |
| title_fullStr | Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome |
| title_full_unstemmed | Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome |
| title_short | Mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with Down syndrome |
| title_sort | mechanisms of progression of myeloid preleukemia to transformed myeloid leukemia in children with down syndrome |
| work_keys_str_mv | AT labuhnm mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT perkinsk mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT matzks mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT varghesel mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT garnettc mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT papaemmanuile mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT metznerm mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT kennedya mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT amstislavskiyv mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT rischt mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT bhayadiar mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT samulowskid mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT hernandezd mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT stoilovab mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT iotchkovav mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT oppermannu mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT scheerc mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT yoshidak mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT schwarzera mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT taubj mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT crispinoj mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT weissm mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT hayashia mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT tagat mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT itoe mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT ogawas mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT reinhardtd mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT yaspom mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT campbellp mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT robertsi mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT constantinescus mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT vyasp mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT heckld mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome AT klusmannj mechanismsofprogressionofmyeloidpreleukemiatotransformedmyeloidleukemiainchildrenwithdownsyndrome |