SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

Zipin-Roitman, Adi; Aqaqe, Nasma; Yassin, Muhammad; Biechonski, Shahar; Amer, Mariam; Delft, Mark F. van; Gan, Olga I.; McDermott, Sean; Buzina, Alla; Ketela, Troy; Shlush, Liran I.; Xie, Stephanie Z.; Voisin, Véronique; Moffat, Jason; Minden, Mark D.; Dick, John E.; Milyavsky, Michael

doi:10.18632/oncotarget.15147

Cited by 17 publications

(23 citation statements)

References 76 publications

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“…SMYD2 is directly activated by the transcription factor MYC, and ablation of SMYD2 impedes the development of leukemia promoted by the fusion oncogene MLL-AF9 [77]. In addition, SMYD2 knockdown confers relative resistance of human acute myeloid leukemia cells to multiple classes of DNA damaging agents, which is associated with the compensatory upregulation of SET7/9 [78]. Similarly, in chronic lymphocytic leukemia (CLL) patients, SMYD2 and SMYD3 are overexpressed, accompanied by a high white blood cell count and complex karyotype [79].…”

Section: Smyd2 In Cancermentioning

confidence: 99%

Histone methyltransferase SMYD2: ubiquitous regulator of disease

Yi¹,

Jiang²,

Fang

2019

Clin Epigenet

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SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2 (SMYD2) is a protein methyltransferase that methylates histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) and diverse nonhistone proteins. SMYD2 activity is required for normal organismal development and the regulation of a series of pathophysiological processes. Since aberrant SMYD2 expression and its dysfunction are often closely related to multiple diseases, SMYD2 is a promising candidate for the treatment of these diseases, such as cardiovascular disease and cancer. Here, we present an overview of the complex biology of SMYD2 and its family members and their context-dependent nature. Then, we discuss the discovery, structure, inhibitors, roles, and molecular mechanisms of SMYD2 in distinct diseases, with a focus on cardiovascular disease and cancer.

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Section: Smyd2 In Cancermentioning

confidence: 99%

Histone methyltransferase SMYD2: ubiquitous regulator of disease

Yi¹,

Jiang²,

Fang

2019

Clin Epigenet

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“…In two select cases, we performed targeted variant-to-function analyses to gain mechanistic insights into disease predisposition, starting with the missense variant in CHEK2. CHEK2 has been previously shown to modulate genotoxic responses in leukemia, but its role in primary human HSPCs had not been studied 40 . Importantly, the lead risk variant (I157T) in our study has been associated with increased risk for other cancers and shown to be a hypomorphic allele with functionally impaired activation of downstream effectors 41,42 .…”

Section: Main Textmentioning

confidence: 99%

“…Importantly, the lead risk variant (I157T) in our study has been associated with increased risk for other cancers and shown to be a hypomorphic allele with functionally impaired activation of downstream effectors 41,42 . Knowing this, we utilized previously characterized methods to suppress its activity or expression 40 . Consistent with observations made in leukemia cells, we found that CHEK2 inhibition reduced genotoxicity upon irradiation of primitive human Lin -CD34 + CD38cells, as compared to more differentiated progenitors (Extended Data Fig.…”

Section: Main Textmentioning

confidence: 99%

“…The following pLKO-puro lentiviral shRNA constructs from the RNAi consortium shRNA library (TRC, https://portals.broadinstitute.org/gpp/public/) were used: shCHEK2 (TRCN0000039946) and shControl (TRCN0000231746). This shRNA has been shown to induce knockdown of total and phosphorylated CHEK2 protein 40 . Viral particles pseudotyped with VSV-G were prepared using transient transfection of 293T cells as described elsewhere 68 .…”

Section: Viral Constructs Human Cd34 + Transduction and Expansion Asmentioning

confidence: 99%

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Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology

Bao

Nandakumar

Liao

et al. 2019

Preprint

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3Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive production of mature myeloid cells that result from the acquisition of somatic driver mutations in hematopoietic stem cells (HSCs) 1 . While substantial progress has been made to define the causal somatic mutation profile for MPNs 2 , epidemiologic studies indicate a significant heritable component for the disease that is among the highest known for all cancers 3 . However, only a limited set of genetic risk loci have been identified, and the underlying biological mechanisms leading to MPN acquisition remain unexplained. Here, to define the inherited risk profile, we conducted the largest genome-wide association study of MPNs to date (978,913 individuals with 3,224 cases) and identified 14 genome-wide significant loci, as well as a polygenic signature that increases the odds for disease acquisition by nearly 3-fold between the top and median deciles. Interestingly, we find a shared genetic architecture between MPN risk and several hematopoietic traits spanning distinct lineages, as well as an association between increased MPN risk and longer leukocyte telomere length, collectively implicating HSC function and self-renewal. Strikingly, we find a significant enrichment for risk variants mapping to accessible chromatin in HSCs compared with other hematopoietic populations. Finally, gene mapping identifies modulators of HSC biology and targeted variant-to-function analyses suggest likely roles for CHEK2 and GFI1B in altering HSC function to confer disease risk. Overall, we demonstrate the power of human genetic studies to illuminate a previously unappreciated mechanism for MPN risk through modulation of HSC function. 4 Main Text:We initially sought to characterize the germline genetic architecture that confers risk for MPNs, and therefore conducted a genome-wide association study (GWAS) meta-analysis using three population-based cohorts (UK Biobank (UKBB), 23andMe, and FinnGen). The combined sample size comprised 2,627 MPN cases and 755,476 controls, more than doubling the number of cases from prior studies (Supplementary Table 1, Extended Data Fig. 1). We tested 7,329,649 well-represented variants passing central and studyspecific quality control measures. Linkage disequilibrium score regression (LDSC) 4 showed negligible inflation in test statistics due to population structure, with an intercept of 1.005 and genomic control factor of 1.0255. We estimate the narrow-sense heritability for MPN risk to be 0.0717 (s.e. = 0.0306) on the liability scale, suggesting that ~7% of variance in MPN risk can be attributed to common genetic variation (MAF > 1%), assuming a disease prevalence of 0.0328%, as reported in population studies 5,6 .Analysis of GWAS signals using GCTA 7 revealed 12 linkage disequilibrium (LD)independent loci at genome-wide significance (p < 5 x 10 -8 ) and an additional 16 loci with suggestive associations (p < 1 x 10 -6 ) ( Fig. 1a, Supplementary Table 2). Previous studies have shown that carriers of the somatic JAK2 V617...

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“…SMYD2 was found to be a potential oncogene in the development of various tumors [ 11 ]. It was also reported that SMYD3 is involved in the invasion of cancer cells and is overexpressed in hepatocellular carcinoma and colorectal cancer [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of SET and MYND Domain-Containing Protein 2 (SMYD2) Is Associated with Tumor Progression and Poor Prognosis in Patients with Papillary Thyroid Carcinoma

Chen

Xiao

et al. 2018

Med Sci Monit

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BackgroundsSET and MYND domain-containing protein 2 (SMYD2), which is identified as a protein-lysine methyltransferase, plays a crucial role in the progression of some tumors such as bladder carcinoma. However, the clinical significance of SMYD2 in patients with papillary thyroid carcinoma (PTC) has not been elucidated. In the present study, we aimed to investigate the expression and role of SMYD2 in human PTC.Material/MethodsClinicopathological analysis was performed in 107 patients with PTC. Expression of SMYD2 was determined by immunohistochemistry staining, quantitative RT-PCR, or Western blotting in PTC tissues, adjacent normal tissues, and PTC cells (K1 and B-CPAP). The prognostic value of SMYD2 in PTC patients was assessed by univariate and multivariate analysis. Clinical outcomes were evaluated by Kaplan-Meier log-rank tests. Cell proliferation was examined in PTC cells following overexpression or knockdown of SMYD2.ResultsSMYD2 was highly expressed in PTC tissues compared to adjacent thyroid tissues. Additionally, high expression of SMYD2 was significantly related to tumor size, lymph node metastasis, and TNM stage. Moreover, SMYD2 was identified as an independent prognosis factor by multivariate analysis. Using 2 PTC cell lines, K1 and B-CPAP, we demonstrated that high expression of SMYD2 can promote tumor cell proliferation.ConclusionsSMYD2 expression was upregulated in PTC tissues and significantly related to the poorer prognosis of PTC patients. Our studies suggested the potential role of SMYD2 as a new therapeutic target and prognostic biomarker in human PTC.

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SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress

Cited by 17 publications

References 76 publications

Histone methyltransferase SMYD2: ubiquitous regulator of disease

Histone methyltransferase SMYD2: ubiquitous regulator of disease

Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology

Overexpression of SET and MYND Domain-Containing Protein 2 (SMYD2) Is Associated with Tumor Progression and Poor Prognosis in Patients with Papillary Thyroid Carcinoma

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