TY - JOUR
T1 - Smyd2 is a Myc-regulated gene critical for MLL-AF9 induced leukemogenesis
AU - Bagislar, Sevgi
AU - Sabò, Arianna
AU - Kress, Theresia R.
AU - Doni, Mirko
AU - Nicoli, Paola
AU - Campaner, Stefano
AU - Amati, Bruno
PY - 2016
Y1 - 2016
N2 - The Smyd2 protein (Set- and Mynd domain containing protein 2) is a methyltransferase that can modify both histones and cytoplasmic proteins. Smyd2 is overexpressed in several cancer types and was shown to be limiting for tumor development in the pancreas. However, genetic evidence for a role of Smyd2 in other cancers or in mouse development was missing to date. Using germ line-deleted mouse strains, we now show that Smyd2 and the related protein Smyd3 are dispensable for normal development. Ablation of Smyd2 did not affect hematopoiesis, but retarded the development of leukemia promoted by MLL-AF9, a fusion oncogene associated with acute myeloid leukemia (AML) in humans. Smyd2-deleted leukemic cells showed a competitive disadvantage relative to wild-type cells, either in vitro or in vivo. The Smyd2 gene was directly activated by the oncogenic transcription factor Myc in either MLL9-AF9-induced leukemias, Myc-induced lymphomas, or fibroblasts. However, unlike leukemias, the development of lymphomas was not dependent upon Smyd2. Our data indicate that Smyd2 has a critical role downstream of Myc in AML.
AB - The Smyd2 protein (Set- and Mynd domain containing protein 2) is a methyltransferase that can modify both histones and cytoplasmic proteins. Smyd2 is overexpressed in several cancer types and was shown to be limiting for tumor development in the pancreas. However, genetic evidence for a role of Smyd2 in other cancers or in mouse development was missing to date. Using germ line-deleted mouse strains, we now show that Smyd2 and the related protein Smyd3 are dispensable for normal development. Ablation of Smyd2 did not affect hematopoiesis, but retarded the development of leukemia promoted by MLL-AF9, a fusion oncogene associated with acute myeloid leukemia (AML) in humans. Smyd2-deleted leukemic cells showed a competitive disadvantage relative to wild-type cells, either in vitro or in vivo. The Smyd2 gene was directly activated by the oncogenic transcription factor Myc in either MLL9-AF9-induced leukemias, Myc-induced lymphomas, or fibroblasts. However, unlike leukemias, the development of lymphomas was not dependent upon Smyd2. Our data indicate that Smyd2 has a critical role downstream of Myc in AML.
KW - Acute myeloid leukemia
KW - C-Myc
KW - Lymphoma
KW - MLL-AF9
KW - Smyd2
UR - http://www.scopus.com/inward/record.url?scp=84994029397&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994029397&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.12012
DO - 10.18632/oncotarget.12012
M3 - Article
AN - SCOPUS:84994029397
VL - 7
SP - 66398
EP - 66415
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 41
ER -