Loss of ISWI ATPase SMARCA5 (SNF2H) in Acute Myeloid Leukemia Cells Inhibits Proliferation and Chromatid Cohesion

Abstract

ISWI chromatin remodeling ATPase SMARCA5 (SNF2H) is a well-known factor for its role in regulation of DNA access via nucleosome sliding and assembly. SMARCA5 transcriptionally inhibits the myeloid master regulator PU.1. Upregulation of SMARCA5 was previously observed in CD34+ hematopoietic progenitors of acute myeloid leukemia (AML) patients. Since high levels of SMARCA5 are necessary for intensive cell proliferation and cell cycle progression of developing hematopoietic stem and progenitor cells in mice, we reasoned that removal of SMARCA5 enzymatic activity could affect the cycling or undifferentiated state of leukemic progenitor-like clones. Indeed, we observed that CRISPR/cas9-mediated SMARCA5 knockout in AML cell lines (S5KO) inhibited the cell cycle progression. We also observed that the SMARCA5 deletion induced karyorrhexis and nuclear budding as well as increased the ploidy, indicating its role in mitotic division of AML cells. The cytogenetic analysis of S5KO cells revealed the premature chromatid separation. We conclude that deleting SMARCA5 in AML blocks leukemic proliferation and chromatid cohesion.

Circulating microRNAs Suggest Networks Associated with Biological Functions in Aggressive Refractory Type 2 Celiac Disease

“…TNRC6B and MYC are also active in gene-expression regulation [ 10 , 40 ], defined by GO:0040029, SMARCA5 (the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 5), and TRIM71 (the tripartite motif containing 71). In this context, SMARCA5 regulates the access to DNA and is upregulated in acute myeloid leukemia [ 41 ], while TRIM71 is a post-transcriptional repressor involved in the cell cycle maintaining embryonic stem cell growth and in the processing of the presentation of class I MHC-mediated antigen [ 42 ]. CPEB3 is another post-transcriptional regulator that controls the polyadenine tail of mRNA and interferes with different biological functions (GO:0001101, GO:0010608, and GO:0050769) [ 43 ].…”

Chromatin Remodeler Smarca5 Is Required for Cancer-Related Processes of Primary Cell Fitness and Immortalization

“…Moreover, interference with cohesin function has been shown to impede DNA repair [ 83 , 84 ] and several genes involved in sister chromatid cohesion are downregulated in our data. Chromosomal aberrations, polyploidy [ 34 ] and cohesion defects [ 85 ], all of which are linked to genomic stability, have been reported in the absence of Smarca5. We also observed the downregulation of genes involved in telomere maintenance.…”

“…Loss of Smarca5 also impacts sensitivity to radiation exposure [ 33 ] and gene expression of DNA repair genes [ 24 , 30 ]. It also causes chromosomal aberrations [ 34 ], indicative of genomic instability [ 35 ]. Hence, Smarca5 has a major impact on pathways involved in cell transformation, cancer development and evolution.…”

DOT1L bridges transcription and heterochromatin formation at pericentromeres

“…Heightened major satellite transcription due to DOT1L upregulation may contribute to tumor severity or progression in these cancers. Notably, SMARCA5 has also been implicated in pathogenesis of acute myeloid leukemia (AML), and like DOT1L is required for hematopoiesis (Kokavec et al, 2017;Stopka and Skoultchi, 2003;Zikmund et al, 2020). Future work will be important to better understand the potential role of DOT1L-mediated regulation of major satellite transcription in cancer.…”