Combined Cohesin–RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes

Ochi, Yotaro; Kon, Ayana; Sakata, Toyonori; Nakagawa, Masahiro; Nakazawa, Naotaka; Kakuta, Masanori; Kataoka, Keisuke; Koseki, Haruhiko; Nakayama, Manabu; Morishita, Daisuke; Tsuruyama, Tatsuaki; Saiki, Ryunosuke; Yoda, Akinori; Okuda, Rurika; Yoshizato, Tetsuichi; Yoshida, Kenichi; Shiozawa, Yusuke; Nannya, Yasuhito; Kotani, Shunsuke; Kogure, Yasunori; Kakiuchi, Nobuyuki; Nishimura, T; Makishima, Hideki; Malcovati, Luca; Yokoyama, Akihiko; Takeuchi, Kengo; Sugihara, Eiji; Sato, Taka Aki; Sanada, Masashi; Takaori‐Kondo, Akifumi; Cazzola, Mario; Kengaku, Mineko; Miyano, Satoru; Shirahige, Katsuhiko; Suzuki, Hiroshi; Ogawa, Seishi

doi:10.1158/2159-8290.cd-19-0982

Cited by 65 publications

(76 citation statements)

References 73 publications

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“…Recently, Ochi et al provided insight to this question discovering a functional relationship between STAG2 and RUNX1 in regulating chromatin structure and gene expression in hematopoietic cells. 90 The authors examined the effects of Runx1 and Stag2 double knockout in a mouse model. Interestingly, all mice that were transplanted with double knockout-derived bone marrow cells developed MDS within 6 mo, while none of the single knockout animals did, experimentally verifying that Runx1 and cohesin mutations cooperate to drive disease development.…”

Section: Mutations That Cooperate With Cohesinmentioning

confidence: 99%

“…Such loops were predominantly associated with genes that exhibit a high rate of transcriptional pausing, such as p53 pathway and interferon response genes as well as some involved in ribosomal translation and DNA repair. 90 Thus, STAG2 and RUNX1 co-mutation may result in the deregulation of a specific set of genes that are critical for maintaining DNA stability and mounting an appropriate immune response to transformed cells.…”

Section: Mutations That Cooperate With Cohesinmentioning

confidence: 99%

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A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

et al. 2021

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Acute myeloid leukemia (AML) affects tens of thousands of patients a year, yet survival rates are as low as 25% in certain populations. This poor survival rate is partially due to the vast genetic diversity of the disease. Rarely do 2 patients with AML have the same mutational profile, which makes the development of targeted therapies particularly challenging. However, a set of recurrent mutations in chromatin modifiers have been identified in many patients, including mutations in the cohesin complex, which have been identified in up to 20% of cases. Interestingly, the canonical function of the cohesin complex in establishing sister chromatid cohesin during mitosis is unlikely to be the affected role in leukemogenesis. Instead, the cohesin complex's role in DNA looping and gene regulation likely facilitates disease. The epigenetic mechanisms by which cohesin complex mutations promote leukemia are not completely elucidated, but alterations of enhancer-promoter interactions and differential histone modifications have been shown to drive oncogenic gene expression changes. Such changes commonly include HoxA upregulation, which may represent a common pathway that could be therapeutically targeted. As cohesin mutations rarely occur alone, examining the impact of common co-occurring mutations, including those in NPM1, the core-binding factor complex, FLT3, and ASXL1, will yield additional insight. While further study of these mutational interactions is required, current research suggests that the use of combinatorial genetics could be the key to uncovering new targets, allowing for the treatment of AML patients based on their individual genetic profiles.

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Section: Mutations That Cooperate With Cohesinmentioning

confidence: 99%

Section: Mutations That Cooperate With Cohesinmentioning

confidence: 99%

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

et al. 2021

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“…The mechanism underlying clonal expansion of these driver mutations is unlikely related to defects in sister chromatid cohesion given lack of association between STAG2 mutations and complex karyotype and aneuploidy (10,18). STAG1-versus STAG2-containing complexes have been recently shown to differentially contribute to chromatin organization, facilitating longer loops at topologically associating domain (TAD) boundaries and shorter more transient nested enhancerpromoter contacts, respectively (19)(20)(21)(22). Furthermore, Stag2/Runx1 deficiency has been shown to disrupt enhancer-promoter looping and effect transcriptional pausing leading to selective gene dysregulation (22).…”

Section: Introductionmentioning

confidence: 99%

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

Tóthová¹,

Valton²,

Gorelov³

et al. 2021

JCI Insight

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The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2–mutant ( STAG2 -mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 ( Tet2 ) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.

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“…MDS is a clonal hematopoietic disorder characterized by bone marrow failure that can develop into acute myeloid leukemia (AML). MDS progression involves multiple signaling pathways [ 1 , 18 ]. We found that YSQHP potentially targets the apoptosis, cell cycle, p53, PI3K-AKT, and MAPK pathways in MDS.…”

Section: Discussionmentioning

confidence: 99%

“…Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological disorders characterized by bone marrow (BM) dysplasia, abnormal myeloid cell differentiation, peripheral blood cytopenia, and an increased risk of leukemic transformation [ 1 ]. MDS results in poor clinical outcomes, and the duration of patient survival is less than 2 years for the higher risk subtypes [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology‐Based Strategy

Han

Song²,

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Background. Yisui Qinghuang powder (YSQHP) is an effective traditional Chinese medicinal formulation used for the treatment of myelodysplastic syndromes (MDS). However, its pharmacological mechanism of action is unclear. Materials and Methods. In this study, the active compounds of YSQHP were screened using the traditional Chinese medicine systems pharmacology (TCMSP) and HerDing databases, and the putative target genes of YSQHP were predicted using the STITCH and DrugBank databases. Then, we further screened the correlative biotargets of YSQHP and MDS. Finally, the compound-target-disease (C-T-D) network was conducted using Cytoscape, while GO and KEGG analyses were conducted using R software. Furthermore, DDI-CPI, a web molecular docking analysis tool, was used to verify potential targets and pathways. Finally, binding site analysis was performed to identify core targets using MOE software. Results. Our results identified 19 active compounds and 273 putative target genes of YSQHP. The findings of the C-T-D network revealed that Rb1, CASP3, BCL2, and MAPK3 showed the most number of interactions, whereas indirubin, tryptanthrin, G-Rg1, G-Rb1, and G-Rh2 showed the most number of potential targets. The GO analysis showed that 17 proteins were related with STPK activity, PUP ligase binding, and kinase regulator activity. The KEGG analysis showed that PI3K/AKT, apoptosis, and the p53 pathways were the main pathways involved. DDI-CPI identified the top 25 proteins related with PI3K/AKT, apoptosis, and the p53 pathways. CASP8, GSK3B, PRKCA, and VEGFR2 were identified as the correlative biotargets of DDI-CPI and PPI, and their binding sites were found to be indirubin, G-Rh2, and G-Rf. Conclusion. Taken together, our results revealed that YSQHP likely exerts its antitumor effects by binding to CASP8, GSK3B, PRKCA, and VEGFR2 and by regulating the apoptosis, p53, and PI3K/AKT pathways.

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Combined Cohesin–RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes

Cited by 65 publications

References 73 publications

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology‐Based Strategy

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