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

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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.

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Tumor spectrum analysis in p53-mutant mice.

T Jacks, L Remington, B Williams … (1994)

The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung and brain. Individuals who inherit one mutant allele of p53 are susceptible to a wide range of tumor types. The gene encodes a transcriptional regulator that may function in the cellular response to DNA damage. The construction of mouse strains carrying germline mutations of p53 facilitates analysis of the function of p53 in normal cells and tumorigenesis. In order to study the effects of p53 mutation in vivo, we have constructed a mouse strain carrying a germline disruption of the gene. This mutation removes approximately 40% of the coding capacity of p53 and completely eliminates synthesis of p53 protein. As observed previously for a different germline mutation of p53, animals homozygous for this p53 deletion mutation are viable but highly predisposed to malignancy. Heterozygous animals also have an increased cancer risk, although the distribution of tumor types in these animals differs from that in homozygous mutants. In most cases, tumorigenesis in heterozygous animals is accompanied by loss of the wild-type p53 allele. We reaffirm that p53 function is not required for normal mouse development and conclude that p53 status can strongly influence tumor latency and tissue distribution.

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Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.

Frank Rosenbauer, Katharina Wagner, Jeffery Kutok … (2004)

Transcription factors are believed to have a dominant role in acute myeloid leukemia (AML). This idea is supported by analysis of gene-knockout mice, which uncovered crucial roles of several transcription factors in normal hematopoiesis, and of individuals with leukemia, in whom transcription factors are frequently downregulated or mutated. However, analysis of knockout animals has not shown a direct link between abrogated transcription factors and the pathogenesis of AML. Sfpi1, encoding the lineage-specific transcription factor PU.1, is indispensable for normal myeloid and lymphoid development. We found that mice carrying hypomorphic Sfpi1 alleles that reduce PU.1 expression to 20% of normal levels, unlike mice carrying homo- or heterozygous deletions of Sfpi1, developed AML. Unlike complete or 50% loss, 80% loss of PU.1 induced a precancerous state characterized by accumulation of an abnormal precursor pool retaining responsiveness to G-CSF with disruption of M- and GM-CSF pathways. Malignant transformation was associated with a high frequency of clonal chromosomal changes. Retroviral restoration of PU.1 expression rescued myeloid differentiation of mutant progenitors and AML blasts. These results suggest that tightly graded reduction, rather than complete loss, of a lineage-indispensable transcription factor can induce AML.

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Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors

Darko Barišić, Michael Stadler, Mario Iurlaro … (2019)

Chromatin remodelling complexes evict, slide, insert or replace nucleosomes, which represent an intrinsic barrier for access to DNA. These remodellers function in most aspects of genome utilization including transcription-factor binding, DNA replication and repair1,2. Although they are frequently mutated in cancer3, it remains largely unclear how the four mammalian remodeller families (SWI/SNF, ISWI, CHD and INO80) orchestrate the global organization of nucleosomes. Here we generated viable embryonic stem cells that lack SNF2H, the ATPase of ISWI complexes, enabling study of SNF2H cellular function, and contrast it to BRG1, the ATPase of SWI/SNF. Loss of SNF2H decreases nucleosomal phasing and increases linker lengths, providing in vivo evidence for an ISWI function in ruling nucleosomal spacing in mammals. Systematic analysis of transcription-factor binding reveals that these remodelling activities have specific effects on binding of different transcription factors. One group critically depends on BRG1 and contains the transcriptional repressor REST, whereas a non-overlapping set of transcription factors, including the insulator protein CTCF, relies on SNF2H. This selectivity readily explains why chromosomal folding and insulation of topologically associated domains requires SNF2H, but not BRG1. Collectively, this study shows that mammalian ISWI is critical for nucleosomal periodicity and nuclear organization and that transcription factors rely on specific remodelling pathways for correct genomic binding.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 18 March 2020

Publication date Collection: March 2020

Volume: 21

Issue: 6

Electronic Location Identifier: 2073

Affiliations

[1 ]Biocev, 1st Medical Faculty, Charles University, 25250 Vestec, Czech Republic; tomzikmund@ 123456gmail.com (T.Z.); paszekova.helena@ 123456gmail.com (H.P.); juraj.kokavec@ 123456gmail.com (J.K.); shefalithakur.st@ 123456gmail.com (S.T.); tereza.turkova@ 123456volny.cz (T.T.); petra-tauchmanova@ 123456seznam.cz (P.T.)

[2 ]Department of Medicine III, University Hospital, LMU Munich, D-80539 Munich, Germany; paul.kerbs@ 123456med.uni-muenchen.de (P.K.); pgreif@ 123456med.uni-muenchen.de (P.A.G.)

[3 ]German Cancer Consortium (DKTK), partner site Munich, D-80336 Munich, Germany

[4 ]German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany

Author notes

[* ]Correspondence: tstopka@ 123456lf1.cuni.cz ; Tel.: +420-32587-3001

[†]

These authors contributed equally.

Author information

Tomas Zikmund https://orcid.org/0000-0003-2452-3749

Helena Paszekova https://orcid.org/0000-0002-6479-6592

Tomas Stopka https://orcid.org/0000-0001-7236-6894

Article

Publisher ID: ijms-21-02073

DOI: 10.3390/ijms21062073

PMC ID: 7139293

PubMed ID: 32197313

SO-VID: 8e95583f-c840-4f76-8264-a7fdb531b7bb

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 26 February 2020

Date accepted : 16 March 2020

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

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Stress signalling in stem cells

Most cited references 28

Tumor spectrum analysis in p53-mutant mice.

Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.

Mammalian ISWI and SWI/SNF selectively mediate binding of distinct transcription factors

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