Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

Viny, Aaron D.; Ott, Christopher J.; Spitzer, Barbara; Rivas, Martín A.; Meydan, Cem; Papalexi, Efthymia; Yelin, Dana; Shank, Kaitlyn; Reyes, Jaime M.; Chiu, April; Romin, Yevgeniy; Boyko, Vitaly; Thota, Swapna; Maciejewski, Jaroslaw P.; Melnick, Ari; Bradner, James E.; Levine, Ross L.

doi:10.1083/jcb.2111oia226

Cited by 35 publications

(63 citation statements)

References 34 publications

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“…However, T47D cells also exhibited severe cell cycle delay following PCI-34051 treatment such that we could not exclude indirect effects of cell cycle arrest on transcription (data not shown). Differences in transcriptional responses between cell types could also be cohesion dose-dependent (12).…”

Section: Hdac8 Inhibition Does Not Mimic Cohesin Depletion In Mcf7mentioning

confidence: 99%

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

Dasgupta

Antony

Braithwaite

et al. 2016

Journal of Biological Chemistry

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Cohesin, a multi-subunit protein complex involved in chromosome organization, is frequently mutated or aberrantly expressed in cancer. Multiple functions of cohesin, including cell division and gene expression, highlight its potential as a novel therapeutic target. The SMC3 subunit of cohesin is acetylated (ac) during S phase to establish cohesion between replicated chromosomes. Following anaphase, ac-SMC3 is deacetylated by HDAC8. Reversal of SMC3 acetylation is imperative for recycling cohesin so that it can be reloaded in interphase for both non-mitotic and mitotic functions. We blocked deacetylation of ac-SMC3 using an HDAC8-specific inhibitor PCI-34051 in MCF7 breast cancer cells, and examined the effects on transcription of cohesin-dependent genes that respond to estrogen. HDAC8 inhibition led to accumulation of ac-SMC3 as expected, but surprisingly, had no influence on the transcription of estrogen-responsive genes that are altered by siRNA targeting of RAD21 or SMC3. Knockdown of RAD21 altered estrogen receptor ␣ (ER) recruitment at SOX4 and IL20, and affected transcription of these genes, while HDAC8 inhibition did not. Rather, inhibition of HDAC8 delayed cell cycle progression, suppressed proliferation and induced apoptosis in a concentration-dependent manner. We conclude that HDAC8 inhibition does not change the estrogen-specific transcriptional role of cohesin in MCF7 cells, but instead, compromises cell cycle progression and cell survival. Our results argue that candidate inhibitors of cohesin function may differ in their effects depending on the cellular genotype and should be thoroughly tested for predicted effects on cohesin's mechanistic roles.The cohesin complex is a chromatin-associated multi-subunit protein comprised of two SMC (structural maintenance of chromosomes, SMC1A and SMC3) 2 and two non-SMC subunits (RAD21, STAG1/2). Cohesin's canonical function establishes cohesion between replicated sister chromatids, thus ensuring their precise segregation at anaphase (1, 2). Research over the last one and a half decades has revealed that cohesin has additional cohesion-independent functions in interphase nuclei, such as chromatin organization and transcription regulation (3, 4).Recently, cancer genome sequencing projects have revealed that genes encoding cohesin subunits are frequently mutated in several different types of cancer, with particularly high frequency in acute myeloid leukemia (AML) (5-9). Recent mouse models indicate that cohesin contributes to leukemia progression likely through controlling transcription and genome organization, rather than through chromosome separation (10 -12). In breast cancer, the cohesin subunit RAD21 is overexpressed and confers poor prognosis (13,14). We previously showed that cohesin mediates transcription of the MYC gene (15-17) and modulates the transcription of estrogen-dependent genes in MCF7 breast cancer cells (18). The emergence of cohesin as an important contributor to cancer has generated interest in the development of therapeutics that compromise ...

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Section: Hdac8 Inhibition Does Not Mimic Cohesin Depletion In Mcf7mentioning

confidence: 99%

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

Dasgupta

Antony

Braithwaite

et al. 2016

Journal of Biological Chemistry

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“…Interestingly, the former function appears irrelevant in AML, with cohesin gene mutations being associated with noncomplex and normal karyotype, and recent murine models implicating altered transcriptional regulation in the development of leukemia. [106][107][108][109] Examination of a large cohort of younger adults with AML identified mutations in 6% of non-APL patients; mutations were found to be mutually exclusive and commonly associated with NPM1c, with no impact on prognosis. 25 Cohesin complex gene mutations are also detected in 10% to 15% of MDS and 20% of secondary AML patients, being associated with mutations involving RUNX1, BCOR, and ASXL1.…”

Section: Mutations In Cohesin Complex Membersmentioning

confidence: 99%

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Grimwade

Ivey

Huntly

2016

Blood

375

300

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Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response.

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“…Stag2 and Stag1 co-deletion is synthetic lethal. 5 The observation that Stag2-deficient HSCs displayed increased self-renewal is in contrast to the lethality observed with loss of the core cohesin component Smc3 in hematopoietic cells (19). We next sought to evaluate potential compensatory function among the Stag paralogs.…”

mentioning

confidence: 99%

Stag1 and Stag2 regulate cell fate decisions in hematopoiesis through non-redundant topological control

Viny

Bowman

Liu

et al. 2019

Preprint

Self Cite

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Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show Stag2 deletion in hematopoietic stem/progenitor cells (HSPC) results in altered hematopoietic function, increased selfrenewal, and impaired differentiation. ChIP-sequencing revealed that while Stag2 and Stag1 can bind the same loci, a component of Stag2 binding sites are unoccupied by Stag1 even in Stag2-deficient HSPCs. While concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to blunted HSPC commitment to the B-cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.One Sentence Summary: Stag1 rescues topologically associated domains in the absence of Stag2, but cannot restore chromatin architecture required for hematopoietic lineage commitment 3 Main textCell-type specific transcriptional programs are regulated in part by the activity of tissue-specific transcription factors and enhancer elements within structurally defined topologically associating domains (TADs) (1-3). The genes which contribute to transcriptional regulation, including members of the cohesin complex, are frequently mutated in human cancers, including 5 leukemias(4-9). Cohesin is a tripartite ring comprised of three structural proteins SMC1A, SMC3, and RAD21; this core complex binds to either STAG1 or STAG2. STAG2, which is an X-linked gene, is the most commonly mutated cohesin complex member in human cancer, with recurrent nonsense, frameshift, and missense mutations in Ewing's Sarcoma (40-60%)(9), bladder cancer (20-35%)(7, 8), glioblastoma (4-5%)(7), myelodysplastic syndrome (MDS)(5-20%)(5, 6), and 10 acute myeloid leukemia (AML)(2-12%)(5). This is in contrast to SMC1A, SMC3, and RAD21, which are more commonly mutated in myeloid malignancies than in a broad spectrum of human cancers. The cohesin complex is essential in pleiotropic cellular and gene regulatory functions, including chromosome segregation(10, 11) and in the formation of DNA loops (3,(12)(13)(14) which regulate gene expression (13,15, 16). However, the high mutational frequency and unique 15 mutational spectrum of STAG2 in human cancers(5-7) suggests a distinct role in homeostasis and tumor suppression(17, 18) which has not been delineated.

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Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

Cited by 35 publications

References 34 publications

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells

Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Stag1 and Stag2 regulate cell fate decisions in hematopoiesis through non-redundant topological control

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