Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagno...Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagnosed entity due to its rarity and the non-standardized practice of lymph node biopsy in CLL. Purpose: The aims of our work are to establish the diagnosis of A-CLL and to study the prognosis and treatment of this rare entity. Method: here, we report the clinical presentation and the follow up of two cases of A-CLL. Results: Distinguishing Richter transformation (RT) from A-CLL is important as it may result in a major change in disease management. The prognosis of A-CLL is intermediate between CLL and RT. The prognosis is mainly poor due to a predominance of poor prognostic markers including an increasing number of p53-positive cases. Conclusion: To this date, no prospective study has been led to define the best treatment for A-CLL. The shorter survival of A-CLL when compared to typical CLL implies the need of a more aggressive treatment.展开更多
Objective: This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia (CLL) and a 17p deletion (17p-) and identify the predictive factors within this subgroup. Methods: The sam...Objective: This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia (CLL) and a 17p deletion (17p-) and identify the predictive factors within this subgroup. Methods: The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 1 lq22, 13q14 and 17p13; trisomy of bands 12q13; and translocation involving band 14q32. The data from 456 patients with or without a 17p- were retrospectively collected and analyzed. Results: The overall response rate (ORR) in patients with a 17p- was 56.9%, and patients with a high percentage of 17p- (defined as more than 25% of cells harbouring a 17p-) had a lower ORR. The median overall survival (OS) in patients with a 17p- was 78.0 months, which was significantly shorter than the OS in patients without this genetic abnormality (median 162.0 months, P〈0.001). Within the subgroup with a 17p-, the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase (LDH), B symptoms, unmutated IGHVand a high percentage of 17p-. Conclusions: These results indicated that patients with a 17p- CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.展开更多
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(...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.展开更多
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 remai...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.展开更多
Non-Hodgkin’s lymphoma cell leukemia (NHLCL),chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HLC) are the diseases very similar to each other. The differential diagnosis is very difficult,especially when ...Non-Hodgkin’s lymphoma cell leukemia (NHLCL),chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HLC) are the diseases very similar to each other. The differential diagnosis is very difficult,especially when there are small lymphoid cells in Periphcral blood and bone marrow under light microscope. We have observed 34 cases with electron microscope. The studies were correlated with clinical manifestation, cytology, pathology and immunologic histochemistry. Ultrastructural features strongly indicated the difference in three various diseases, although all the immunologic markers showed B-cell type.It is concluded that electron microscopic examination is of a definite significance in the diaguosis and successful treatment.展开更多
Summary: The variable heavy chain region (VH) genes of 3 untreated patients with B cell chronic lymphocytic leukemia (B CLL) were cloned and analyzed. The VH family used was VH3 11, VH3 72 and VH3 33. More than 2...Summary: The variable heavy chain region (VH) genes of 3 untreated patients with B cell chronic lymphocytic leukemia (B CLL) were cloned and analyzed. The VH family used was VH3 11, VH3 72 and VH3 33. More than 2 % difference from the corresponding germline gene was detected in all the 3 obtained potential functional genes (average 16.7). Mutation pattern analysis indicated evidence of antigen selective pressure observed in 1 of 3 cases. Our findings suggested that the tumor cells originate from post GC cells.展开更多
BACKGROUND Langerhans cell sarcoma(LCS)is a rare malignancy with poor prognosis.LCS and chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL)can occur in the same diseased tissues,such as lymph nodes or sk...BACKGROUND Langerhans cell sarcoma(LCS)is a rare malignancy with poor prognosis.LCS and chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL)can occur in the same diseased tissues,such as lymph nodes or skin.CASE SUMMARY A 48-year-old female Han Chinese patient was admitted for generalized lymph node enlargement for 6 years and abdominal distension for 1 wk.She was diagnosed with small B-cell lymphoma(stage IV)/CLL(Benet stage B)and received chemotherapy.She started oral ibrutinib in February 2019.She was hospitalized on June 11,2019,and a 1.5 cm×1.5 cm dark-red nodule with ulceration scalp lesion was found.Biopsy revealed LCS but without CLL/SLL.She was diagnosed with CLL/SLL(Binet stage C,Rai stage IV)accompanied by secondary histiocytic sarcomas and skin LCS and received cyclophosphamide,doxorubicin,vincristine,dexamethasone,and etoposide but developed severe cytopenia.She ultimately refused treatments and discharged spontaneously.She died on September 12,2019.The literature review showed that in patients with CLL/SLL,skin lesions of LCS are accompanied by CLL/SLL.This patient was different from the previously reported cases of skin LCS in patients with CLL/SLL.CONCLUSION In this patient,the skin lesion of LCS showed no concomitant CLL/SLL.展开更多
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. Obs...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.展开更多
The expression vector of SmIg scFv fragment was constructed in patient with B cell chronic lymphocyte leukemia (B-CLL) and expressed in E. coli to obtain scFv fragment, and the effect of the protein on the prolifera...The expression vector of SmIg scFv fragment was constructed in patient with B cell chronic lymphocyte leukemia (B-CLL) and expressed in E. coli to obtain scFv fragment, and the effect of the protein on the proliferation of stimulated peripheral blood mononuclear cells (PBMC) was investigated in vitro. Two pairs of primers were designed, and variable region genes of light chain and heavy chain were amplified by PCR respectively from the pGEM-T vectors previously constructed in our laboratory which containing light chain gene or Fd fragment of heavy chain gene. The PCR product was digested, purified and inserted into pHEN2 vector to construct the soluble expression vector pHEN2-scFv. After the induction by IPTG, the scFv protein was identified by SDS- PAGE electrophoresis and purified by Ni-NTA-Chromatography. MTT was used to determine the effect of purified protein on the proliferation of stimulated PBMC in vitro. Plasmid PCR and restriction enzyme digestion of pHEN2-scFv revealed the pHEN2-scFv vector was constructed successfully. Id-scFv protein was expressed in positive clone after induced by IPTG. SDS-PAGE analysis showed that the relative molecular weight of fusion protein was about 30 kD (1 kD= 0. 9921 ku), which was consistent with the theoretically predicted value. Proliferation of PBMC could be induced by purified Id-scFv. It was suggested that the expression vector of SmIg scFv fragment was constructed successfully, and scFv protein was expressed and secreted from E. coil, which could induce proliferation of PBMC. This may lay an experimental foundation for further research of Id- HSP complex vaccine for B-CLL.展开更多
White Blood Cell(WBC)cancer or leukemia is one of the serious cancers that threaten the existence of human beings.In spite of its prevalence and serious consequences,it is mostly diagnosed through manual practices.The...White Blood Cell(WBC)cancer or leukemia is one of the serious cancers that threaten the existence of human beings.In spite of its prevalence and serious consequences,it is mostly diagnosed through manual practices.The risks of inappropriate,sub-standard and wrong or biased diagnosis are high in manual methods.So,there is a need exists for automatic diagnosis and classification method that can replace the manual process.Leukemia is mainly classified into acute and chronic types.The current research work proposed a computer-based application to classify the disease.In the feature extraction stage,we use excellent physical properties to improve the diagnostic system’s accuracy,based on Enhanced Color Co-Occurrence Matrix.The study is aimed at identification and classification of chronic lymphocytic leukemia using microscopic images of WBCs based on Enhanced Virtual Neural Network(EVNN)classification.The proposed method achieved optimum accuracy in detection and classification of leukemia from WBC images.Thus,the study results establish the superiority of the proposed method in automated diagnosis of leukemia.The values achieved by the proposed method in terms of sensitivity,specificity,accuracy,and error rate were 97.8%,89.9%,76.6%,and 2.2%,respectively.Furthermore,the system could predict the disease in prior through images,and the probabilities of disease detection are also highly optimistic.展开更多
Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and nontarget cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal ...Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and nontarget cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal antibodies (Mab) directed against human chronic lymphocytic leukemia (CLL), Dal B01 and Dal B02, by an active ester method. Both conjugates were more cytotoxic toward the target tumor cell line D101 than to the nontarget cell line MOLT3, and Dal B02MTX conjugate was more inhibitory to D101 cells than free MTX in a 6 h pulse exposure assay. Results: Drug uptake studies revealed that D101 cells took up much more Dal B01 and Dal B02conjugated MTX than free MTX. The amounts of drug taken up by D101 cells incubated with Dal B01 and Dal B02conjugated MTX were always 3 to 5fold higher than that taken up by MOLT3 cells, although the latter took up more drug when incubated with free MTX. Furthermore, tumor cells incubated with Dal B01 or Dal B02conjugated MTX retained much larger amounts of drug for a prolonged period of time than those incubated with free MTX. Conclusion: The enhanced specific cytotoxicity of Dal B01 and Dal B02MTX conjugates toward target tumor cells is therefore likely due to (I) delivery of larger amounts of MTX to target cells when the drug is conjugated to Mab; (ii) longer retention of Mabconjugated MTX by target cells; and (iii) slow, prolonged release of MTX from the surfacebound or endocytosed conjugates, rendering them into a sustained release dosage form.展开更多
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...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.展开更多
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 decade...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, 36.0 months and 19.0 months, respectively, P 〈 0.001 ). Conclusions: This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.展开更多
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 ly...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±4.60)%and(19.72±1.10)%,respectively(P<0.05 for both).The apoptosis rate was reduced after knocking down TOSO in the primary CLL cells.In addition,we also found that TOSO down-regulation in primary cells from CLL patients led to decreased expression of BCL-2 as well as lower apoptosis,and vice versa in the cell line.Conclusions:TOSO might be involved in the pathogenesis of CLL by interacting with SYK,enhancing the BCR signaling pathway,and inducing apoptosis resistance.展开更多
Objective To summarize the recent findings of dysregulation of signaling pathways and miRNAs in chronic lymphocytic leukemia (CLL). Data sources We searched PubMed database with the keywords "chronic lymphocytic le...Objective To summarize the recent findings of dysregulation of signaling pathways and miRNAs in chronic lymphocytic leukemia (CLL). Data sources We searched PubMed database with the keywords "chronic lymphocytic leukemia", "signal pathway", or "miRNA" for relevant articles in recent years.展开更多
Coexistence of chronic lymphocytic leukemia (CLL) and essential thrombocythemia (ET) in a patient is extremely rare, with only 10 cases reported thus far in literature. This paper describes a 94-year-old male havi...Coexistence of chronic lymphocytic leukemia (CLL) and essential thrombocythemia (ET) in a patient is extremely rare, with only 10 cases reported thus far in literature. This paper describes a 94-year-old male having atypical B-CLL with CD5- (CD5-) phenotype and ET. In this patient, we performed interphase fluorescence in situ hybridization (FISH) analysis which revealed 13q14.3 deletion in 31% of B-lymphocyte nuclei and RB1 deletion in 27% of B-lymphocyte nuclei, but not in neutrophils and T-lymphocytes. Furthermore, we identified JAK2 V617F mutation in the peripheral blood nucleated cells and neutrophils, but not in the B- and T-lymphocyte populations. Therefore, it was concluded that the occurrence of CD5- B-CLL and ET in this patient was pathogenically independent.展开更多
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 chemoimmunoth...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.展开更多
In this paper,we study the dynamical behavior of a stochastic two-compartment model of B-cell chronic lymphocytic leukemia,which is perturbed by white noise.Firstly,by constructing suitable Lyapunov functions,we estab...In this paper,we study the dynamical behavior of a stochastic two-compartment model of B-cell chronic lymphocytic leukemia,which is perturbed by white noise.Firstly,by constructing suitable Lyapunov functions,we establish sufficient conditions for the existence of a unique ergodic stationary distribution.Then,conditions for extinction of the disease are derived.Furthermore,numerical simulations are presented for supporting the theoretical results.Our results show that large noise intensity may contribute to extinction of the disease.展开更多
Cell karyotyping in patients with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is not easy to success, and small genomic lesions (〈5 Mb) are not routinely detected by this method. It is likel...Cell karyotyping in patients with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is not easy to success, and small genomic lesions (〈5 Mb) are not routinely detected by this method. It is likely that a complete genomic characterization of CLL requires a combination of fluorescence in situ hybridization (FISH), single nucleotide polymorphism (SNP) array profiling for comprehensive genome-wide analysis of acquired genomic copy number aberrations (aCNAs) and loss-of-heterozygosity (LOH) in dominant clones, and karyotyping for detection of balanced translocations, isochromosomes, and marker chromosomes. SNP array analysis can reveal chromothripsis, a phenomenon by which regions of the cancer genome are shattered and recombined to generate frequent oscillations between the lower and the higher DNA copy number states. This study provided cytogenetic findings in a CLL/SLL patient with v-myc avian myelocytomatosis viral oncogene homolog (C-MYC)-amplification by FISH, in which SNP arrays detected profound genomic upheaval due to chromothripsis that may lead to malignant transformation.展开更多
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 reg...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.展开更多
文摘Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagnosed entity due to its rarity and the non-standardized practice of lymph node biopsy in CLL. Purpose: The aims of our work are to establish the diagnosis of A-CLL and to study the prognosis and treatment of this rare entity. Method: here, we report the clinical presentation and the follow up of two cases of A-CLL. Results: Distinguishing Richter transformation (RT) from A-CLL is important as it may result in a major change in disease management. The prognosis of A-CLL is intermediate between CLL and RT. The prognosis is mainly poor due to a predominance of poor prognostic markers including an increasing number of p53-positive cases. Conclusion: To this date, no prospective study has been led to define the best treatment for A-CLL. The shorter survival of A-CLL when compared to typical CLL implies the need of a more aggressive treatment.
基金supported by grants from the National Nature Science Foundation of China (No. 81200395, 81370632)the National Science and Technology supporting Program (No. 2014BAI09B12)+1 种基金the Fundamental Application and Advanced Technology Research Program of Tianjin (No. 15JCYBJC27900)the National Public Health Grand Research Foundation (No. 201202017)
文摘Objective: This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia (CLL) and a 17p deletion (17p-) and identify the predictive factors within this subgroup. Methods: The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 1 lq22, 13q14 and 17p13; trisomy of bands 12q13; and translocation involving band 14q32. The data from 456 patients with or without a 17p- were retrospectively collected and analyzed. Results: The overall response rate (ORR) in patients with a 17p- was 56.9%, and patients with a high percentage of 17p- (defined as more than 25% of cells harbouring a 17p-) had a lower ORR. The median overall survival (OS) in patients with a 17p- was 78.0 months, which was significantly shorter than the OS in patients without this genetic abnormality (median 162.0 months, P〈0.001). Within the subgroup with a 17p-, the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase (LDH), B symptoms, unmutated IGHVand a high percentage of 17p-. Conclusions: These results indicated that patients with a 17p- CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.
基金grants from the National Natural Science Foundation of China(No.81970146)National Science Foundation of China International Cooperation and Exchange Program(No.81720108002)+1 种基金National Science and Technology Major Project(No.2018ZX09734007)Six Talent Peaks Project in Jiangsu Province,2019(No.WSN-001).
文摘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.
文摘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.
文摘Non-Hodgkin’s lymphoma cell leukemia (NHLCL),chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HLC) are the diseases very similar to each other. The differential diagnosis is very difficult,especially when there are small lymphoid cells in Periphcral blood and bone marrow under light microscope. We have observed 34 cases with electron microscope. The studies were correlated with clinical manifestation, cytology, pathology and immunologic histochemistry. Ultrastructural features strongly indicated the difference in three various diseases, although all the immunologic markers showed B-cell type.It is concluded that electron microscopic examination is of a definite significance in the diaguosis and successful treatment.
基金a grantfrom the NationalNature Science Foundation of China (Serial No.3 0 0 70 3 2 5 )Nature Science Foundation of Hubei Province
文摘Summary: The variable heavy chain region (VH) genes of 3 untreated patients with B cell chronic lymphocytic leukemia (B CLL) were cloned and analyzed. The VH family used was VH3 11, VH3 72 and VH3 33. More than 2 % difference from the corresponding germline gene was detected in all the 3 obtained potential functional genes (average 16.7). Mutation pattern analysis indicated evidence of antigen selective pressure observed in 1 of 3 cases. Our findings suggested that the tumor cells originate from post GC cells.
文摘BACKGROUND Langerhans cell sarcoma(LCS)is a rare malignancy with poor prognosis.LCS and chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma(SLL)can occur in the same diseased tissues,such as lymph nodes or skin.CASE SUMMARY A 48-year-old female Han Chinese patient was admitted for generalized lymph node enlargement for 6 years and abdominal distension for 1 wk.She was diagnosed with small B-cell lymphoma(stage IV)/CLL(Benet stage B)and received chemotherapy.She started oral ibrutinib in February 2019.She was hospitalized on June 11,2019,and a 1.5 cm×1.5 cm dark-red nodule with ulceration scalp lesion was found.Biopsy revealed LCS but without CLL/SLL.She was diagnosed with CLL/SLL(Binet stage C,Rai stage IV)accompanied by secondary histiocytic sarcomas and skin LCS and received cyclophosphamide,doxorubicin,vincristine,dexamethasone,and etoposide but developed severe cytopenia.She ultimately refused treatments and discharged spontaneously.She died on September 12,2019.The literature review showed that in patients with CLL/SLL,skin lesions of LCS are accompanied by CLL/SLL.This patient was different from the previously reported cases of skin LCS in patients with CLL/SLL.CONCLUSION In this patient,the skin lesion of LCS showed no concomitant CLL/SLL.
文摘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.
文摘The expression vector of SmIg scFv fragment was constructed in patient with B cell chronic lymphocyte leukemia (B-CLL) and expressed in E. coli to obtain scFv fragment, and the effect of the protein on the proliferation of stimulated peripheral blood mononuclear cells (PBMC) was investigated in vitro. Two pairs of primers were designed, and variable region genes of light chain and heavy chain were amplified by PCR respectively from the pGEM-T vectors previously constructed in our laboratory which containing light chain gene or Fd fragment of heavy chain gene. The PCR product was digested, purified and inserted into pHEN2 vector to construct the soluble expression vector pHEN2-scFv. After the induction by IPTG, the scFv protein was identified by SDS- PAGE electrophoresis and purified by Ni-NTA-Chromatography. MTT was used to determine the effect of purified protein on the proliferation of stimulated PBMC in vitro. Plasmid PCR and restriction enzyme digestion of pHEN2-scFv revealed the pHEN2-scFv vector was constructed successfully. Id-scFv protein was expressed in positive clone after induced by IPTG. SDS-PAGE analysis showed that the relative molecular weight of fusion protein was about 30 kD (1 kD= 0. 9921 ku), which was consistent with the theoretically predicted value. Proliferation of PBMC could be induced by purified Id-scFv. It was suggested that the expression vector of SmIg scFv fragment was constructed successfully, and scFv protein was expressed and secreted from E. coil, which could induce proliferation of PBMC. This may lay an experimental foundation for further research of Id- HSP complex vaccine for B-CLL.
文摘White Blood Cell(WBC)cancer or leukemia is one of the serious cancers that threaten the existence of human beings.In spite of its prevalence and serious consequences,it is mostly diagnosed through manual practices.The risks of inappropriate,sub-standard and wrong or biased diagnosis are high in manual methods.So,there is a need exists for automatic diagnosis and classification method that can replace the manual process.Leukemia is mainly classified into acute and chronic types.The current research work proposed a computer-based application to classify the disease.In the feature extraction stage,we use excellent physical properties to improve the diagnostic system’s accuracy,based on Enhanced Color Co-Occurrence Matrix.The study is aimed at identification and classification of chronic lymphocytic leukemia using microscopic images of WBCs based on Enhanced Virtual Neural Network(EVNN)classification.The proposed method achieved optimum accuracy in detection and classification of leukemia from WBC images.Thus,the study results establish the superiority of the proposed method in automated diagnosis of leukemia.The values achieved by the proposed method in terms of sensitivity,specificity,accuracy,and error rate were 97.8%,89.9%,76.6%,and 2.2%,respectively.Furthermore,the system could predict the disease in prior through images,and the probabilities of disease detection are also highly optimistic.
文摘Objective: To analysis the uptake of free MTX and MTX conjugated to tumor specific monoclonal antibody by target and nontarget cells. Methods: The folate antagonist methotrexate (MTX) was conjugated to two monoclonal antibodies (Mab) directed against human chronic lymphocytic leukemia (CLL), Dal B01 and Dal B02, by an active ester method. Both conjugates were more cytotoxic toward the target tumor cell line D101 than to the nontarget cell line MOLT3, and Dal B02MTX conjugate was more inhibitory to D101 cells than free MTX in a 6 h pulse exposure assay. Results: Drug uptake studies revealed that D101 cells took up much more Dal B01 and Dal B02conjugated MTX than free MTX. The amounts of drug taken up by D101 cells incubated with Dal B01 and Dal B02conjugated MTX were always 3 to 5fold higher than that taken up by MOLT3 cells, although the latter took up more drug when incubated with free MTX. Furthermore, tumor cells incubated with Dal B01 or Dal B02conjugated MTX retained much larger amounts of drug for a prolonged period of time than those incubated with free MTX. Conclusion: The enhanced specific cytotoxicity of Dal B01 and Dal B02MTX conjugates toward target tumor cells is therefore likely due to (I) delivery of larger amounts of MTX to target cells when the drug is conjugated to Mab; (ii) longer retention of Mabconjugated MTX by target cells; and (iii) slow, prolonged release of MTX from the surfacebound or endocytosed conjugates, rendering them into a sustained release dosage form.
文摘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.
基金This work was supported by grants from the National Natural Science Foundation of China (No. 81370632, 81200395), the National Science and Technology Supporting Program (No. 2014BAI09B 12), the Fundamental Application and Advanced Technology Research Program of Tianjin (No. 15JCYBJC27900), and the National Public Health Grand Research Foundation (No. 201202017).
文摘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, 36.0 months and 19.0 months, respectively, P 〈 0.001 ). Conclusions: This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.
基金This work was supported by grants from the National Nature Science Foundation of China(Nos.81200395 and 81970187)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences grants(No.2017-I2M-3-018)Fundamental Application and Advanced and Technology Research Program of Tianjin(No.15JCYBJC25100)。
文摘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±4.60)%and(19.72±1.10)%,respectively(P<0.05 for both).The apoptosis rate was reduced after knocking down TOSO in the primary CLL cells.In addition,we also found that TOSO down-regulation in primary cells from CLL patients led to decreased expression of BCL-2 as well as lower apoptosis,and vice versa in the cell line.Conclusions:TOSO might be involved in the pathogenesis of CLL by interacting with SYK,enhancing the BCR signaling pathway,and inducing apoptosis resistance.
基金This study was supported by the grants from the National Natural Science Foundation (No. 81270598), Natural Science Foundation of Shandong Province, China (No. Y2007C053, No. ZR2009CM059), and the Scientific &Technological Project of Shandong Province, China (No. 2007GG 10002008).
文摘Objective To summarize the recent findings of dysregulation of signaling pathways and miRNAs in chronic lymphocytic leukemia (CLL). Data sources We searched PubMed database with the keywords "chronic lymphocytic leukemia", "signal pathway", or "miRNA" for relevant articles in recent years.
文摘Coexistence of chronic lymphocytic leukemia (CLL) and essential thrombocythemia (ET) in a patient is extremely rare, with only 10 cases reported thus far in literature. This paper describes a 94-year-old male having atypical B-CLL with CD5- (CD5-) phenotype and ET. In this patient, we performed interphase fluorescence in situ hybridization (FISH) analysis which revealed 13q14.3 deletion in 31% of B-lymphocyte nuclei and RB1 deletion in 27% of B-lymphocyte nuclei, but not in neutrophils and T-lymphocytes. Furthermore, we identified JAK2 V617F mutation in the peripheral blood nucleated cells and neutrophils, but not in the B- and T-lymphocyte populations. Therefore, it was concluded that the occurrence of CD5- B-CLL and ET in this patient was pathogenically independent.
基金National Natural Science Foundation of China(Nos. 81700193, 81970146, 82170186, and 81720108002)National Major Science and Technology Projects of China(No. 2018ZX09734-007)+1 种基金China Postdoctoral Science Foundation(No. 2021M691336)Jiangsu Postdoctoral Science Foundation(No. 2021K083A)。
文摘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.
基金This work is supported by the National Natural Science Foundation of China(No.11871473)Natural Science Foundation of Shandong Province(No.ZR2019MA010)Science and Technology Research Project of Jilin Provincial Department of Education of China(No.JJKH20180462KJ).
文摘In this paper,we study the dynamical behavior of a stochastic two-compartment model of B-cell chronic lymphocytic leukemia,which is perturbed by white noise.Firstly,by constructing suitable Lyapunov functions,we establish sufficient conditions for the existence of a unique ergodic stationary distribution.Then,conditions for extinction of the disease are derived.Furthermore,numerical simulations are presented for supporting the theoretical results.Our results show that large noise intensity may contribute to extinction of the disease.
基金Source of Support: This study was supported by grants from Natural Science Foundation of China (No. 81100379 and No. 81302079), Science and Technology Planning Project of Guangdong Province, China (No. 2013B022000102), Medical Scientific Research Foundation of Guangdong Province, China (No. A2014292) and Key Clinical Disciplines of Guangdong Province (No. 20111219).
文摘Cell karyotyping in patients with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) is not easy to success, and small genomic lesions (〈5 Mb) are not routinely detected by this method. It is likely that a complete genomic characterization of CLL requires a combination of fluorescence in situ hybridization (FISH), single nucleotide polymorphism (SNP) array profiling for comprehensive genome-wide analysis of acquired genomic copy number aberrations (aCNAs) and loss-of-heterozygosity (LOH) in dominant clones, and karyotyping for detection of balanced translocations, isochromosomes, and marker chromosomes. SNP array analysis can reveal chromothripsis, a phenomenon by which regions of the cancer genome are shattered and recombined to generate frequent oscillations between the lower and the higher DNA copy number states. This study provided cytogenetic findings in a CLL/SLL patient with v-myc avian myelocytomatosis viral oncogene homolog (C-MYC)-amplification by FISH, in which SNP arrays detected profound genomic upheaval due to chromothripsis that may lead to malignant transformation.
基金supported by grants SAF2009-07035,SAF2012-31613,SAF2015-69180-R,PI060400,RD06/0020/0011,RD12/0036/0061(to García-Pardo A)and SAF2017-86327-R(to Redondo-Muñoz J)from the Ministerio de Ciencia e Innovacion-Fondo Europeo de Desarrollo Regional(FEDER),MadridP2010/BMD-2314 from the Comunidad de Madrid/European Union(to García-Pardo A)+1 种基金the Fundación de Investigación Mutua Madrileña(to García-Pardo A)the 2020 Leonardo Grant for Researchers and Cultural Creators(BBVA Foundation)(to Redondo-Muñoz J).
文摘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.