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Overexpression of c-Myc-dependent heterogeneous nuclear ribonucleoprotein A1 promotes proliferation and inhibits apoptosis in NOTCH1-mutated Chronic lymphocytic leukemia cells

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Chinese Medical Journal 2022年第8期135卷 920-929页

作者： Yixin Zou Hanning Tang Yi Miao Huayuan Zhu Li Wang Lei Fan Jianxin Fu Wei Xu Jianyong Li Yi Xia department of Hematology The First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjingJiangsu 210029China Key Laboratory of Hematology of Nanjing Medical University NanjingJiangsu 210029China Collaborative Innovation Center for Cancer Personalized Medicine NanjingJiangsu 210029China Pukou CLL Center NanjingJiangsu 210000China

Background: NOTCH1 mutation is an essential molecular biologic aberration in Chronic lymphocytic leukemia (CLL). CLL patients withNOTCH1 mutation have shown an unfavorable survival and a poor response to chemoimmunotherapy. This study aims to present the mechanisms of adverse prognosis caused byNOTCH1 mutation from the perspective of the splicing factor heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1).Methods: The microarray data in Gene Expression Omnibus datasets were analyzed by bioinformatics and the function of hnRNPA1 was checked by testing the proliferation and apoptosis of CLL-like cell lines. Afterward, quantitative reverse transcription-polymerase chain reaction and Western blotting were applied to explore the relationship among NOTCH1, c-Myc, and hnRNPA1.Results: RNA splicing was found to play a vital part inNOTCH1-mutated CLL cells;hence, hnRNPA1 was selected as the focus of this study. Higher expression of hnRNPA1 validated in primaryNOTCH1-mutated CLL samples could promote proliferation and inhibit apoptosis in CLL. The expression of hnRNPA1 increased when NOTCH1 signaling was activated by transfection with NOTCH1 intracellular domain (NICD)-overexpressed adenovirus vector and declined after NOTCH1 signaling was inhibited by NOTCH1-shRNA. Higher expression of c-Myc was observed in NICD-overexpressed cells and hnRNPA1 expression was downregulated after applying c-Myc inhibitor 10058-F4. Moreover, in NICD-overexpressed cells, hnRNPA1 expression decreased through c-Myc inhibition.Conclusion: Overexpression of c-Myc-dependent hnRNPA1 could promote proliferation and inhibit apoptosis inNOTCH1- mutated CLL cells, which might partly account for the poor prognosis of patients withNOTCH1 mutation.

关键词： Chronic lymphocytic leukemia NOTCH1 mutation c-Myc Heterogeneous nuclear ribonucleoprotein A1

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TOSO interacts with SYK and enhances BCR pathway activation in Chronic lymphocytic leukemia

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Chinese Medical Journal 2020年第17期133卷 2090-2097页

作者： Yan-Ru Zhang Zhen Yu Wen-Jie Xiong Xu-Xiang Liu Hui-Min Liu Rui Cui Qi Wang Wen-Ming Chen Lu-Gui Qiu Shu-Hua Yi State Key Laboratory of Experimental Hematology National Clinical Research Center for Blood DiseasesInstitute of Hematology and Blood Disease HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300020China Department of Hematology Beijing Chao Yang Hospital Affiliated to Capital Medical UniversityBeijing 100043China Department of Pathology City of Hope National Medical CenterDuarte 91010CAUSA Department of Hematology Tianjin First Center HospitalTianjin 300192China

Background:TOSO,also named Fas inhibitory molecule 3(FAIM3),has recently been identified as an immunoglobulin M(IgM)Fc receptor(FcμR).Previous studies have shown that TOSO is specifically over-expressed in Chronic lymphocytic leukemia(CLL).However,the functions of TOSO in CLL remain unknown.The B-cell receptor(BCR)signaling pathway has been reported to be constitutively activated in CLL.Here,we aimed to investigate the functions of TOSO in the BCR signaling pathway and the pathogenesis of CLL.Methods:We over-expressed TOSO in B-cell lymphoma cell lines(Granta-519 and Z138)by lentiviral transduction and knocked down TOSO by siRNA in primary CLL cells.The over-expression and knockdown of TOSO were confirmed at the RNA level by polymerase chain reaction and protein level by Western blotting.Co-immunoprecipitation with TOSO antibody followed by liquid chromatography coupled with tandem mass spectrometry(IP/LCMS)was used to identify TOSO interacting proteins.Western blotting was performed to detect the activation status of BCR signaling pathways as well as B-cell lymphoma 2(BCL-2).Flow cytometry was used to examine the apoptosis of TOSO-over-expressing B lymphoma cell lines and TOSO-down-regulated CLL cells via the staining of Annexin V and 7-AAD.One-way analyses of variance were used for intergroup comparisons,while independent samples t tests were used for two-sample comparisons.Results:From IP/LCMS,we identified spleen tyrosine kinase(SYK)as a crucial candidate of TOSO-interacting protein and confirmed it by co-immunoprecipitation.After stimulation with anti-IgM,TOSO over-expression increased the phosphorylation of SYK,and subsequently activated the BCR signaling pathway,which could be reversed by a SYK inhibitor.TOSO knockdown in primary CLL cells resulted in reduced SYK phosphorylation as well as attenuated BCR signaling pathway.The apoptosis rates of the Granta-519 and Z138 cells expressing TOSO were(8.46±2.90)%and(4.20±1.21)%,respectively,significantly lower than the rates of the control groups,which were(25.20

关键词： Chronic lymphocytic leukemia TOSO B-cell receptor signaling pathway SYK Apoptosis

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Chronic lymphocytic leukemia Prognostic Index： A New Inteorated Scorino System to Predict the Time to First Treatment in Chinese Patients with chronic lymphocytic leukemia

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Chinese Medical Journal 2017年第2期130卷 135-142页

作者： Heng Li Shu-Hua Yi Wen-Jie Xiong Hui-Min Liu Rui Lyu Ting-Yu Wang Wei Liu Shi-Zhen Zhong Zhen Yu De-Hui Zou Yan Xu Gang An Zeng-Jun Li Lu-Gui Qiu Department of Lymphoma and Myeloma State Key Laboratory of Experimental Hematology Institute of Hematology and Blood Disease Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin 300041 China

Background： The established clinical staging systems （Rai/Binet） of Chronic lymphocytic leukemia （CLL） cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together, To predict the time to first treatment （TTFT） in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index （CLL-PI）. Methods： Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region （1GI：tV） in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. Results： The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages （P 〈 0.001） or with 11q- （P = 0.002）, 17p- （P 〈 0.001）, unmutated IGHV （P 〈 0.001）, negative 13q- （P = 0.007） and elevated lactate dehydrogenase levels （P = 0.001 ） tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified： advanced clinical stage （P = 0.002）, 17p- （P = 0.050） and unmutated 1GHV （P = 0.049）. Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize tbur different risk groups （low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]） with significantly different TTFT （median TTFT of not reached （NR）, 65.0 months, 36

关键词： 17p Deletion Chronic lymphocytic leukemia Immunoglobulin Heavy Chain Variable Mutation Prognostic Index Timeto First Treatment

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Cytogenetic characteristics of B cell Chronic lymphocytic leukemia in 275 Chinese patients by fluorescence in situ hybridization： a multicenter study

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Chinese Medical Journal 2011年第16期124卷 2417-2422页

作者： LAI Yue-yun HUANG Xiao-jun Peking University Institute of Hematology Peking UniversityPeople's Hospital Beijing Key Laboratory of Hematopoietic StemCell Transplantation Beijing 100044 China

Background Under conventional cytogenetic （CC） analysis, only 30%-50% of B cell Chronic lymphocytic leukemia （B-CLL） cases show clonal aberrations. Using fluorescence in situ hybridization （FISH）, the percentage of patients with abnormalities rises to almost 80%, among them, the most frequent abnormalities were 13q14, 1 lq22, p53 deletions and trisomy 12. The aim of this study was to explore the incidence of cytogenetic changes in Chinese patients with B-CLL. Methods We used FISH methods to detect the cytogenetic features in 275 cases of B-CLL from 48 hospitals. The correlation between FISH abnormalities and clinical characteristics such as age, gender, white blood cell count, peripheral hemoglobin （Hb） level, peripheral platelet count （PLT）, lactate dehydrogenase （LDH） level, Rai stage, Binet stage, and overall survival was analyzed, and the relationship between them and overall survival was also analyzed to evaluate their prognostic implications. Results Of the 275 patients, genetic aberrations were found in 77.8% using FISH. The frequencies of abnormalities were as follows： 13q deletion （56.4%）, trisomy 12 （34.5%）, p53 deletion （33.5%） and 11q22 deletion （30.5%）. It was obvious that the patients with p53 deletion had lower level of Hb （P=0.001） and PLT （P=-0.003） when compared to patients without p53 deletion. Significant differences were obtained in the distribution of p53 deletion according to Rai and Binet classification systems （P=0.016 and 0.008 respectively）. Significant differences were also observed when the overall survival was correlated with p53 deletion （P=-0.043）, Rai stage （P=0.006）, Binet stage （P=0.013）, Hb level （P=-0.004） and PLT level （P=-0.010）. Conclusions Chinese CLL patients have the similar frequencies of del（13q）, trisomy 12, del（11q） and a higher frequency of del（17p） when compared to literatures. Del（17p） is associated with advanced stage and low levels of Hb and PLT. Patients with p53 deletion, or advanced stage probably have poor survival in China.

关键词： cytogenetics Chronic lymphocytic leukemia in situ hybridization, fluorescence

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Synchronous diagnosis and treatment of acute myeloid leukemia and Chronic lymphocytic leukemia:Two case reports

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World Journal of Clinical Cases 2021年第30期9卷 9144-9150页

作者： Rong-Rong Chen Li-Xia Zhu Lu-Lu Wang Xue-Ying Li Jia-Nai Sun Mi-Xue Xie Jing-Jing Zhu De Zhou Jian-Hu Li Xin Huang Wan-Zhuo Xie Xiu-Jin Ye Department of Hematology The First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003Zhejiang ProvinceChina

BACKGROUND The concurrence of acute myeloid leukemia(AML)and Chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

关键词： Acute myeloid leukemia Chronic lymphocytic leukemia B-cell lymphoma-2 inhibitors Therapy Ten-eleven translocation-2 Case report

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Time-limited,Combined Regimen in Chronic lymphocytic leukemia:A Promising Strategy to Achieve a Drug Holiday

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Current Medical Science 2021年第3期41卷 431-442页

作者： Rui JIANG Jian-yong LI Hua-yuan ZHU Pukou CLL Center Pukou Division of Jiangsu Province HospitalNanjing 211800China Department of Hematology the First Affiliated Hospital of Nanjing Medical UniversityJiangsu Province HospitalNanjing 210029China Collaborative Innovation Center for Cancer Personalized Medicine Nanjing 210029China

Chemoimmunotherapy(CIT)is defined as standard first line treatment for Chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.

关键词： small molecular targeted agents Bruton's tyrosine kinase inhibitor Chronic lymphocytic leukemia chemoimmunotherapy combination

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Promises and pitfalls of targeted agents in Chronic lymphocytic leukemia

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Cancer Drug Resistance 2020年第3期3卷 415-444页

作者： Thomas E.Lew Mary Ann Anderson John F.Seymour Department of Clinical Haematology The Royal Melbourne Hospital and Peter MacCallum Cancer CentreParkville 3050Australia. Blood Cells and Blood Cancer Division Walter and Eliza Hall Institute of Medical ResearchParkville 3050Australia. Faculty of Medicine Dentistry and Health SciencesThe University of MelbourneParkville 3050Australia.

Targeted agents have significantly improved outcomes for patients with Chronic lymphocytic leukemia,particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy.Two classes of agent in particular,the Bruton tyrosine kinase inhibitors(e.g.,ibrutinib)and the B-cell lymphoma 2 inhibitor,venetoclax,induce high response rates and durable remissions in the relapsed/refractory and frontline settings.However,maturing clinical data have revealed promises and pitfalls for both agents.These drugs induce remissions and disease control in the majority of patients,often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches.Unfortunately,in the relapsed and refractory setting,both agents appear to be associated with an inevitable risk of disease relapse and progression.Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression.Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’quality and length of life.Rational drug combinations,optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.

关键词： Chronic lymphocytic leukemia drug resistance venetoclax B-cell lymphoma 2 ibrutinib bruton tyrosine kinase idelalisib phosphatidylinositol 3-kinase

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Homogenously high expression of CD32b renders it a potential target for CAR-T therapy for Chronic lymphocytic leukemia

Homogenously high expression of CD32b renders it a potential...

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第十四届全国免疫学学术大会

作者： guoling wang xiaolei sun shiyu zuo chuo li qing niu yonghui xia yuan meng min liu zihao fang xi yang yanyu jiang sheng wang haidong cui huifang huang erlie jiang dongming zhou qi deng jing pan xiaoming feng Institut Pasteur of Shanghai Tianjin First Central Hospital Hubei Cancer Hospital The First Affiliated Hospital of School of Medicine of Zhejiang University Fujian Medical University Union Hospital Tianjin Medical University Beijing Boren Hospital

CD19 chimeric antigen receptor(CAR)-T cells have been used to treat patients with refractory Chronic lymphocytic leukemia(CLL).However,approximately 50% of patients do not respond to this therapy.To improve the clinical outcome of these patients,it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy.In this study,we screened a panel of surface antigens and found that CD32 b(FcyRⅡb) was homogeneously expressed at high site density on tumor cells from CLL patients.We then developed a second-generation CAR construct targeting CD32 b,and T cells transduced with the CD32 CAR efficiently eliminated the CD32 bRaji leukemic cell line in vitro and in a mouse xenograft model.Furthermore,CD32 b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice.The efficacy of CD32 b CART cells correlated with the CD32 b density on CLL cells.CD32 b is not significantly expressed by non-B hematopoietic cells,but expressed by several normal tissues and cells.We identified CD32 b as a potential target of CAR-T cell therapy for CLL,although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.

关键词： Chronic lymphocytic leukemia CD32b Chimeric antigen receptor Antigen site density

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Regulation and function of angiogenic factors in Chronic lymphocytic leukemia

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 815-836页

作者： Angeles García-Pardo Javier Redondo-Muñoz Department of Molecular Biomedicine Centro de Investigaciones Biológicas Margarita SalasConsejo Superior de Investigaciones CientíficasMadrid 280140Spain

Progression of Chronic lymphocytic leukemia(CLL)is determined by the localization of malignant cells in lymphoid tissues,where they receive growth and survival signals.CLL cells produce angiogenic factors that are regulated by internal and external stimuli and whose levels vary according to the clinical stage of the disease.Stromal cellular and molecular components in CLL niches disturb the balance of pro-and antiangiogenic molecules in CLL cells and induce an angiogenic switch.Additionally,CLL cells also influence the behavior of microenvironmental cells,inducing endothelial cell proliferation and increasing the angiogenic capacity of macrophages,neutrophils,and other cells present in CLL niches.As a result of these reciprocal functional interactions,bone marrow angiogenesis is frequently increased in CLL and has been proposed as a prognostic marker in early disease.Besides their role in regulating angiogenesis,angiogenic factors are also involved in CLL cell migration and survival,all contributing to disease progression.Angiogenic factors,particularly vascular endothelial growth factor,have therefore been attractive therapeutic targets in CLL and many clinical trials were established in the past years.However,the results of these trials reveal that anti-angiogenic therapies alone are not as efficient as expected and should rather be used in combination with other treatments.

关键词： Chronic lymphocytic leukemia angiogenic factors CLL microenvironment CLL migration and survival antiangiogenic therapy

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Chronic lymphocytic leukemia of del 17p in a Young Subject: About a Case and Reviewed a Literature

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Open Journal of Blood Diseases 2022年第4期12卷 103-109页

作者： Amadou Djibrilla-Almoustapha Moustapha Mamane-Brah Moustapha Elhadj-Chefou Maman Rabiou Badé Faiza Abba-Ousmane Fanta Ousseini Oumoulkairou Abdoulaye-Soumana Badé Malam-Abdou Departement of Onco-Hematology of the National Hospital of Niamey Niamey Niger Faculty of Health Science Abdou Moumouni University of Niamey Niamey Niger Faculty of Health Science André Salifou University of Zinder Zinder Niger Faculty of Health Science of Maradi Maradi Niger

Objective: To report a case of chronic Lymphoid leukemia in a 28-year-old young subject, with variable clinical features and a TP53 mutation, diagnosed and followed up in the Onco-Hematology department of the HNN. Observation: 28-year-old patient, having consulted for polyadenopathy and physical asthenia, whose clinical examination found a conscious patient, submaxillary, laterocervical, axillary and inguinal lymphadenopathy, bilateral, symmetrical, painless and non-compressive whose largest measures 3 cm in diameter. Hepato-splenomegaly and epistaxis. Predominantly lymphocyte hyperleukocytosis, immunophenotyping revealed low CD19+, CD5+, CD23+, CD20 monoclonal B lymphoid proliferation. The Matutes score was 4. A karyotype showed a three-chromosome translocation;the short arm of a chromosome 2, the long arm of a chromosome 11 and the long arm of a chromosome 13, and a translocation between the long arm of a chromosome 6 and the long arm of a chromosome 18. A FISH objectified a led 17p. The diagnosis of Binet Stage C CLL with positive del 17p and complex karyotype was retained. Despite the poor prognosis, the R-C (Rituximab-Chlorambucil) protocol was instituted with once-weekly transfusions. The patient is still alive in partial clinical and biological remission. Conclusion: Despite therapeutic progress, the presence of the deletion of chromosome 17p with TP53 mutation and the young age of the patient does not change the patient’s prognosis.

关键词： Chronic lymphocytic leukemia Young Subject del 17 p HNN Niger

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