TY - JOUR
T1 - Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome
AU - Labuhn, Maurice
AU - Perkins, K.
AU - Matzk, Sören
AU - Varghese, L.
AU - Garnett, Catherine
AU - Papaemmanuil, Elli
AU - Metzner, Marlen
AU - Kennedy, Alison
AU - Amstislavskiy, Vyacheslav
AU - Risch, Thomas
AU - Bhayadia, Raj
AU - Samulowski, D.
AU - Hernandez, David Cruz
AU - Stoilova, Bilyana
AU - Iotchkova, Valentina
AU - Oppermann, Udo
AU - Scheer, Carina
AU - Yoshida, Kenichi
AU - Schwarzer, Adrian
AU - Taub, Jeffrey
AU - Crispino, John D.
AU - Weiss, Mitchell J.
AU - Hayashi, Asuhide
AU - Taga, Takashi
AU - Ito, Etsuro
AU - Ogawa, Seishi
AU - Reinhardt, Dirk
AU - Yaspo, Marie Laure
AU - Campbell, Peter J.
AU - Roberts, I.
AU - Constantinescu, Stefan
AU - Vyas, Paresh
AU - Heckl, Dirk
AU - Klusmann, Jan Henning
N1 - Funding Information:
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.
Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/8/12
Y1 - 2019/8/12
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - CRISPR screen
KW - Down syndrome
KW - GATA1
KW - cancer transformation
KW - preleukemia
UR - http://www.scopus.com/inward/record.url?scp=85070184742&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070184742&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2019.06.007
DO - 10.1016/j.ccell.2019.06.007
M3 - Article
C2 - 31303423
AN - SCOPUS:85070184742
VL - 36
SP - 123-138.e10
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 2
ER -
