Erschienen:
Springer Science and Business Media LLC, 2020
Erschienen in:Oncogene
Sprache:
Englisch
DOI:
10.1038/s41388-020-01495-6
ISSN:
0950-9232;
1476-5594
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression remains to be explored. We found that <jats:italic>SUV39H1</jats:italic> was down-regulated in a variety of leukemias, including <jats:italic>MLL</jats:italic>-r AML, as compared with normal individuals. Decreased levels of <jats:italic>Suv39h1</jats:italic> expression and genomic H3K9me3 occupancy were observed in LSCs from <jats:italic>MLL</jats:italic>-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. <jats:italic>Suv39h1</jats:italic> overexpression increased leukemia latency and decreased the frequency of LSCs in <jats:italic>MLL</jats:italic>-<jats:italic>r</jats:italic> AML mouse models, while <jats:italic>Suv39h1</jats:italic> knockdown accelerated disease progression with increased number of LSCs. Increased <jats:italic>Suv39h1</jats:italic> expression led to the inactivation of <jats:italic>Hoxb13</jats:italic> and <jats:italic>Six1</jats:italic>, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, <jats:italic>Hoxb13</jats:italic> expression is up-regulated in <jats:italic>MLL</jats:italic>-<jats:italic>AF9</jats:italic>-induced AML cells, while knockdown of <jats:italic>Hoxb13</jats:italic> in <jats:italic>MLL</jats:italic>-<jats:italic>AF9</jats:italic> leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies. Our data revealed that SUV39H1 functions as a tumor suppressor in <jats:italic>MLL</jats:italic>-<jats:italic>AF9</jats:italic>-induced AML progression. These findings provide the direct link of SUV39H1 to AML development and progression.</jats:p>