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BRD2 induces drug resistance through activation of the RasGRP1/Ras/ERK signaling pathway in adult t-cell lymphoblastic lymphoma

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Cancer Communications 2020年第6期40卷 245-259页

作者： Xiao-Peng tian Jun Cai Shu-Yun Ma Yu Fang Hui-Qiang Huang tong-Yu Lin Hui-Lan Rao Mei Li Zhong-Jun Xia tie-Bang Kang Dan Xie Qing-Qing Cai State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China Department of Pathology Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China Department of Hematology Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China

Background:Adult patients with t-cell lymphoblastic lymphoma(t-LBL)are treated with high-intensity chemotherapy regimens,but the response rate is still unsatisfactory because of frequent drug *** aimed to investigate the potential mechanisms of drug resistance in adults with ***:Gene expression microarray was used to identify differential mRNA expression profiles between chemotherapy-resistant and chemotherapy-sensitive adult t-LBL ***-time PCR and immunohistochemistry were performed to detect the expression of bromodomain-containing protein 2(BRD2)and c-Myc in fresh-frozen t-LBL tissues from 85 adult *** Ras pull-down assay was performed to monitor Ras *** immunoprecipitation assays were used to analyze the binding of E2F transcription factor 1(E2F1)/BRD2 to the RAS guanyl releasing protein 1(RasGRP1)promoter *** drug resistance effect and mechanism of BRD2 were determined by both in vivo and in vitro ***:A total of 86 chemotherapy resistance-related genes in adult t-LBL were identified by gene expression *** them,BRD2 was upregulated in chemotherapy-resistant adult t-LBL tissues and associated with worse progressionfree survival and overall survival of 85 adult t-LBL ***,BRD2 suppressed doxorubicin(Dox)-induced cell apoptosis both in vitro and in *** activation of RasGRP1/Ras/ERK signaling might contribute to the Dox resistance effect of ***,OtX015,a bromodomain and extra-terminal(BEt)inhibitor,reversed the Dox resistance effect of ***-derived tumor xenograft demonstrated that the sequential use of OtX015 after Dox showed superior therapeutic ***:Our data showed that BRD2 promotes drug resistance in adult t-LBL through the RasGRP1/Ras/ERK signaling *** BRD2 may be a novel strategy to improve the therapeutic efficacy and prolong survival of adults with tLBL.

关键词： t-cell lymphoblastic lymphoma drug resistance BRD2 MEK ERK c-Myc RasGRP1 doxorubicin OtX015 sequential treatment simultaneous treatment

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Genomic landscape of t-cell lymphoblastic lymphoma

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Chinese Journal of Cancer Research 2022年第2期34卷 83-94页

作者： Zhaoming Li Yue Song Mingzhi Zhang Yiming Wei Hang Ruan Department of Oncology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China State Key Laboratory of Esophageal Cancer Prevention&treatment and Henan Key Laboratory for Esophageal Cancer Research the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China

Objective: t-cell lymphoblastic lymphoma(t-LBL) is an aggressive neoplasm of precursor t cells, however,detailed genome-wide sequencing of large t-LBL cohorts has not been performed due to its rarity. the purpose of this study was to identify putative driver genes in ***: to gain insight into the genetic mechanisms of t-LBL development, we performed whole-exome sequencing on 41 paired tumor-normal DNA samples from patients with ***: We identified 32 putative driver genes using whole-exome sequencing in 41 t-LBL cases, many of which have not previously been described in t-LBL, such as Janus kinase 3(JAK3), Janus kinase 1(JAK1), Runtrelated transcription factor 1(RUNX1) and Wilms’ tumor suppressor gene 1(Wt1). When comparing the genetic alterations of t-LBL to t-cell acute lymphoblastic leukemia(t-ALL), we found that JAK-StAt and RAS pathway mutations were predominantly observed in t-LBL(58.5% and 34.1%, respectively), whereas Notch and cell cycle signaling pathways mutations were more prevalent in t-ALL. Notably, besides notch receptor 1(NOtCH1), mutational status of plant homeodomain(PHD)-like finger protein 6(PHF6) was identified as another independent factor for good prognosis. Of utmost interest is that co-existence of PHF6 and NOtCH1 mutation status might provide an alternative for early therapeutic stratification in ***: together, our findings will not only provide new insights into the molecular and genetic mechanisms of t-LBL, but also have tangible implications for clinical practice.

关键词： t-cell lymphoblastic lymphoma PHF6 NOtCH1 mutation

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Cryptic NUP214-ABL1 fusion with complex karyotype, episomes and intra-tumor genetic heterogeneity in a t-cell lymphoblastic lymphoma

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Journal of Cancer Metastasis and treatment 2018年第1期4卷 597-605页

作者： Moneeb A.K Othman Beate Grygalewicz Agnieszka Kołkowska-Lesniak Joana B.Melo Isabel M.Carreira thomas Liehr Jena University Hospital Friedrich Schiller UniversityInstitute of Human GeneticsJena D-07740Germany Cytogenetic Laboratory Maria Sklodowska-Curie Memorial Cancer Centre and InstituteWarsaw 02-781Poland Department of Lymphatic Diseases Institute of Hematology and TransfusionWarsaw 02-776Poland Laboratory of Cytogenetics and Genomics Faculty of MedicineUniversity of CoimbraCoimbra 3000-354Portugal Centro de Investigac̃ao em Meio Ambiente Genetica e Oncobiologia(CIMAGO)Coimbra 3001-301Portugal

t-lymphoblastic lymphoma(t-LBL)is a rare and aggressive form of non-Hodgkin’s lymphoma and little is known about their molecular ***,complex karyotypes were already related to this group of malignancy and associated with poor ***,we describe a 17-year-old female being diagnosed with t-LBL and a normal karyotype after standard G-banding with trypsin-Giemsa(GtG)-***,further analyses including high-resolution molecular approaches,array-comparative genomic hybridization(aCGH),multiplex ligation-dependent probe amplification,fluorescence in situ hybridization and multicolor chromosome banding revealed a cryptic complex karyotype,NUP214-ABL1 gene fusion,episomes and intra-tumor genetic *** addition,homozygous loss of CDKN2A,as well as amplification of oncogene tLX1(HOX11)were ***,NUP214-ABL1 fusion gene replicated autonomously in this case as ***,highly amplification of NUP214-ABL1 fusion gene defines possibly a new subgroup of t-LBL patients which accordingly could benefit from treatment with tyrosine kinase *** episomes are missed in standard karyotyping aCGH should be performed routinely in t-LBL to possibly detect more of such cases.

关键词： t-cell lymphoblastic lymphoma NUP214-ABL1 fusion complex karyotype episomes intra-tumor genetic heterogeneity molecular cytogenetics array comparative genomic hybridization

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Comprehensive view on genetic features, therapeutic modalities and prognostic models in adult t-cell lymphoblastic lymphoma

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Blood Science 2022年第3期4卷 155-160页

作者： Qihua Zou Shuyun Ma Xiaopeng tian Qingqing Cai Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhou 510060P.R.China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060P.R.China

Adult t-cell lymphoblastic lymphoma(t-LBL)is a rare and aggressive subtype of non-Hodgkin’s lymphoma that differs from pediatric t-LBL and has a worse *** to its rarity,little is known about the genetic and molecular characteristics,optimal treatment modalities,and prognostic factors of adult ***,we summarized the existing studies to comprehensively discuss the above issues in this *** mutations of NOtCH1/FBXW7,PtEN,RAS,and KMt2D,together with abnormal activation of signaling pathways,such as the JAK-StAt signaling pathway were *** also discussed the therapeutic *** diagnosed,adult t-LBL patients should receive intensive or pediatric acute lymphoblastic leukemia regimen and central nervous system prophylaxis as soon as possible,and cranial radiation-free protocols are *** radiotherapy improves clinical outcomes,but adverse events are of *** stem cell transplantation may be considered for adult t-LBL patients with high-risk factors or those with relapsed/refractory ***,several novel prognostic models have been constructed,such as the 5-miRNAs-based classifier,11-gene-based classifier,and 4-CpG-based classifier,which have presented significant prognostic value in adult t-LBL.

关键词： Genetic features Prognostic models t-cell lymphoblastic lymphoma therapeutic modalities

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targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in t-cell lymphoblastic lymphoma

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Blood Science 2023年第4期5卷 249-257页

作者： Ning Su Yu Fang Xu Chen Xiaoqin Chen Zhongjun Xia Huiqiang Huang Yi Xia Panpan Liu Xiaopeng tian Qingqing Cai Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhouChina State Key Laboratory of Oncology in South China Collaborative Innovation Center of Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouChina Department of Oncology Guangzhou Chest HospitalGuangzhouChina Guangdong Provincial Key Laboratory of Malignant tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina Department of Oncology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Urology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina Department of Hematology Oncology Sun Yat-sen University Cancer CenterGuangzhouChina

t-cell lymphoblastic lymphoma(t-LBL)is a highly aggressive non-Hodgkin lymphoma with a poor prognosis.P21-activated kinase(PAK)is a component of the gene expression-based classifier that can predict the prognosis of ***,the role of PAK in t-LBL progression and survival remains poorly ***,we found that the expression of PAK1 was significantly higher in t-LBL cell lines(Jurkat,SUP-t1,and CCRF-CEM)compared to the human t-lymphoid cell ***,PAK2 mRNA level of 32 relapsed t-LBL patients was significantly higher than that of 37 cases without relapse(P=.012).t-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression(PAK1,P=.028;PAK2,P=.027;PAK1/2,P=.032).PAK inhibitors,PF3758309(PF)and FRAX597,could suppress the proliferation of t-LBL cells by blocking the G1/S cell cycle phase ***,PF could enhance the chemosensitivity to doxorubicin in vitro and in ***,through western blotting and RNA sequencing,we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1,NF-κB and cell adhesion signaling pathways in t-LBL cell *** findings suggest that PAK might be associated with t-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of t-LBL cells treated with ***,our present study underscores the potential therapeutic effect of inhibiting PAK in t-LBL therapy.

关键词： P21-activated kinase PAK inhibitor Proliferation Relapse t-cell lymphoblastic lymphoma

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