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
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 -