Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

Mullenders, Jasper; Aranda-Orgillés, Beatriz; Lhoumaud, Priscillia; Keller, Matthew D.; Pae, Juhee; Wang, Kun; Kayembe, Clarisse; Rocha, Pedro P.; Raviram, Ramya; Gong, Yixiao; Premsrirut, Prem K.; Tsirigos, Aristotelis; Bonneau, Richard; Skok, Jane A.; Cimmino, Luisa; Hoehn, Daniela; Aifantis, Iannis

doi:10.1084/jem.20151323

Cited by 151 publications

(189 citation statements)

References 67 publications

(89 reference statements)

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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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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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“…, indicating that cohesin mutations may promote tumorigenesis through altering different cohesin functions such as genome organization and transcriptional regulation (Galeev et al, 2016;Mazumdar et al, 2015;Mullenders et al, 2015;Viny et al, 2015). Regardless of the mechanisms driving cohesin mutant tumors, the recent success of poly (ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated ovarian and prostate cancer demonstrates that exploiting tumor suppressor loss by applying the concept of synthetic lethality in defined patient populations can impact clinical cancer care (Castro, Mateo, Olmos, & de Bono, 2016;G.…”

mentioning

confidence: 99%

Synthetic lethality between the cohesin subunitsSTAG1andSTAG2in diverse cancer contexts

Lelij

Lieb

Jude

et al. 2017

Preprint

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. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/155309 doi: bioRxiv preprint first posted online Jun. 25, 2017; 3 Main textCohesin is a highly conserved ring-shaped protein complex that is thought to topologically embrace chromatid fibers (Peters & Nishiyama, 2012), which is essential for sister chromatid cohesion and chromosome segregation in eukaryotes. In addition, cohesin participates in DNA repair, genome organization and gene expression (Losada, 2014). The cohesin subunits SMC1, SMC3 and RAD21 (also called SCC1) comprise the core ring of the complex. A fourth universally conserved subunit, a HEAT repeat protein of the Scc3/STAG family, peripherally associates with the core cohesin ring by binding to RAD21 (Toth et al., 1999), and is required for the dynamic association of cohesin with chromatin (Hu et al., 2011;Murayama & Uhlmann, 2014). Human somatic cells express two paralogs of this protein, called STAG1 and STAG2 (Losada, Yokochi, Kobayashi, & Hirano, 2000;Sumara, Vorlaufer, Gieffers, Peters, & Peters, 2000).Recent cancer genome studies identified recurrent mutations in cohesin subunits and regulators in approximately 7.3% of all human cancers (Lawrence et al., 2014; Leiserson et al., 2015;Solomon et al., 2011). STAG2, the most frequently mutated cohesin subunit, emerges as one of only 12 genes that are significantly mutated in 4 or more major human malignancies (Lawrence et al., 2014). STAG2 mutations have been reported in ~6% of acute myeloid leukemias and myelodysplastic syndromes (Kon et al., 2013; Thota et al., 2014; Walter et al., 2012), 15-22% of Ewing's sarcomas (Brohl et al., 2014; Crompton et al., 2014;Tirode et al., 2014), and in up to 26% of bladder cancers of various stages and grades (Balbas-Martinez et al., 2013; Guo et al., 2013;Solomon et al., 2013;Taylor, Platt, Hurst, Thygesen, & Knowles, 2014). The deleterious nature of most STAG2 mutations strongly suggests that the gene represents a new tumor suppressor . STAG2 mutations were initially thought to promote tumorigenesis due to defects in sister chromatid cohesin leading to genome instability (Barber et al., 2008;Solomon et al., 2011). However, the vast majority of cohesin-mutated cancers are euploid (Balbas-Martinez et . CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/155309 doi: bioRxiv preprint first posted online Jun. 25, 2017; 4 al., 2013;Kon et al., 2013), indicating that cohesin mutations may promote tumorigenesis through altering different cohesin functions such as genome organization and transcriptional regulation (Galeev et al., 2016; Mazumdar et al., 2015;Mullenders et al., 2015; Viny et al., 2015). Regardless of the mechanisms driving cohesin mutant tumors, the recent success of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated o...

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“…Cohesins are molecular glue that function in sister chromatid linkage and gene expression control. Iannis Aifantis (New York University, USA) and Roman Galeev (Larson lab- Lund University, Sweden) showed diminishing cohesion levels, but not complete removal, alters HSC function independent of its effects on cell division 34 . Aifantis’ group then used ATAC (assay for transposase-accessible chromatin)-Seq to demonstrate that the underlying mechanism is likely through alterations in chromatin confirmation, which then leads to increased expression of erythroid lineage genes and a bias toward the granulocyte-monocyte progenitor stage 34 .…”

Section: Beyond the Double Helixmentioning

confidence: 99%

Hematopoiesis “awakens”: Evolving technologies, the force behind them

Flores-Figueroa

Essers

Bowman

2016

Experimental Hematology

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Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

Abstract: Mullenders et al. report that loss of cohesin alters stem cell homeostasis and myelopoiesis, facilitating the development of a myeloid malignancy.

Cited by 151 publications

References 67 publications

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

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

Synthetic lethality between the cohesin subunitsSTAG1andSTAG2in diverse cancer contexts

Hematopoiesis “awakens”: Evolving technologies, the force behind them

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