SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia

Abstract

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 SUV39H1 was down-regulated in a variety of leukemias, including MLL-r AML, as compared with normal individuals. Decreased levels of Suv39h1 expression and genomic H3K9me3 occupancy were observed in LSCs from MLL-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. Suv39h1 overexpression increased leukemia latency and decreased the frequency of LSCs in MLL-r AML mouse models, while Suv39h1 knockdown accelerated disease progression with increased number of LSCs. Increased Suv39h1 expression led to the inactivation of Hoxb13 and Six1, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, Hoxb13 expression is up-regulated in MLL-AF9-induced AML cells, while knockdown of Hoxb13 in MLL-AF9 leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies. Our data revealed that SUV39H1 functions as a tumor suppressor in MLL-AF9-induced AML progression. These findings provide the direct link of SUV39H1 to AML development and progression.

Identification of Key Transcription Factors and Immune Infiltration Patterns Associated With Breast Cancer Prognosis Using WGCNA and Cox Regression Analysis

“…In recent years, an increasing number of studies have found that drugs targeting TFs can modulate some hallmark properties of cancer. For example, MLL-AF9 is a driver of the leukemia stem cell population (7); GABP increases expression of TERT in glioblastomas with a mutant TERT promoter (8); PML-RARa blocks cell differentiation in acute promyelocytic leukemia (9); RUNX1-ETO reduces CD48, thereby decreasing NK cell killing (10); Runx2 and SIX1 induce epithelial-mesenchymal transition (EMT) and breast cell invasion (11,12).…”

Roles of ferroptosis in urologic malignancies

“…Suppressor of variegation 3–9 homolog 1 (SUV39H1), the first characterized mammalian domain-containing histone methyltransferase, catalyzes tri-methylation of histone 3 lysine 9 (H3K9me3) [ 87 ]. It is generally reported to be a tumor suppressor.…”

Structure, Activity and Function of the Suv39h1 and Suv39h2 Protein Lysine Methyltransferases

“…Several lines of evidence documented a tumor suppressive role of SUV39H1 through its stabilization and silencing of heterochromatin. It has been found that SUV39H-deficient mice develop B-cell lymphomas with increased frequencies [ 54 ], and SUV39H1 was observed to be downregulated in many leukemias [ 82 ]. The protective effect of SUV39H1 in leukemia was validated in mouse models using SUV39H1 overexpression or knockdown and the data provided a direct link between SUV39H1 and AML via the silencing of HOXB13 and SIC1 [ 82 ].…”

“…It has been found that SUV39H-deficient mice develop B-cell lymphomas with increased frequencies [ 54 ], and SUV39H1 was observed to be downregulated in many leukemias [ 82 ]. The protective effect of SUV39H1 in leukemia was validated in mouse models using SUV39H1 overexpression or knockdown and the data provided a direct link between SUV39H1 and AML via the silencing of HOXB13 and SIC1 [ 82 ]. Similarly, tumorigenesis driven by Ras or Myc is accelerated by the loss of SUV39H1 [ 83 , 84 ].…”