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.
Highlights
Acute myeloid leukemia (AML) is a malignant hematopoietic disease derived from myeloid-primed stem cells resulting in accumulation of myeloid blasts
We studied how ISWI ATPase SMARCA5/SNF2H controls in AML the proliferation and gene expression of myeloblasts as SMARCA5 appeared to be an interesting target for anti-AML therapy
Our previous work demonstrated a pattern of SMARCA5 upregulation at AML diagnosis followed by its normalization upon achieving the hematologic remission
Summary
Acute myeloid leukemia (AML) is a malignant hematopoietic disease derived from myeloid-primed stem cells resulting in accumulation of myeloid blasts. Targets of mutagenesis are often genes encoding regulators of gene transcription (e.g., RUNX1, CEBPA, GATA2), DNA methylation (e.g., DNMT3A, IDH1, IDH2), and genome organization (e.g., CTCF, RAD21, SMC3). Immature cells during tissue development require ATP-dependent chromatin remodeling activities to ensure accession of regulatory proteins to DNA in order to control replication, transcription, or DNA repair. Smarca ( known as Snf2h) belongs to important enzymes of the Swi2/Snf family with remodeling activity that is required for successful hematopoietic development in mammals [1,2,3]. Our work and the work of others suggested that Smarca facilitates proliferation-associated events and helps to activate transcriptional programs of particular developmental stages to set proper expression identity of immature cells [4,5]. Additional evidence implicated that Smarca regulates global gene expression programs and function of many human gene regulatory elements by cooperating with CTCF [6,7,8]
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