Incidence and Survivability of Acute Lymphocytic Leukemia Patients in the United States: Analysis of SEER Data Set from 2000-2019

The main goal of this research is to assess the impact of race, age at diagnosis, sex, and phenotype on the incidence and survivability of acute lymphocytic leukemia (ALL) among patients in the United States. By taking these factors into account, the study aims to explore how existing cancer registry data can aid in the early detection and effective treatment of ALL in patients. Our hypothesis was that statistically significant correlations exist between race, age at which patients were diagnosed, sex, and phenotype of the ALL patients, and their rate of incidence and survivability data were evaluated using SEER*Stat statistical software from National Cancer Institute. Analysis of the incidence data revealed that a higher prevalence of ALL was among the Caucasian population. The majority of ALL cases (59%) occurred in patients aged between 0 to 19 years at the time of diagnosis, and 56% of the affected individuals were male. The B-cell phenotype was predominantly associated with ALL cases (73%). When analyzing survivability data, it was observed that the 5-year survival rates slightly exceeded the 10-year survival rates for the respective demographics. Survivability rates of African Americans patients were the lowest compared to Caucasian, Asian, Pacific Islanders, Alaskan Native, Native Americans and others. Survivability rates progressively decreased for older patients. Moreover, this study investigated the typical treatment methods applied to ALL patients, mainly comprising chemotherapy, with occasional supplementation of radiation therapy as required. The study demonstrated the considerable efficacy of chemotherapy in enhancing patients’ chances of survival, while those who remained untreated faced a less favorable prognosis from the disease. Although a significant amount of data and information exists, this study can help doctors in the future by diagnosing patients with certain characteristics. It will further assist the health care professionals in screening potential patients and early detection of cases. This could also save the lives of elderly patients who have a higher mortality rate from this disease.

Serum LDH level may predict outcome of chronic lymphocytic leukemia patients with a 17p deletion： a retrospective analysis of prognostic factors in China

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.

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

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.

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

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.

Concomitant Chronic Lymphocytic Leukemia and Multiple Myeloma: Proof of Common Clonal Origin

We describe a patient with concomitant B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). CLL- and MM-cell were separated by preparative flourescence-activated cell sorting (FACS). DNA sequence analysis of the complementarity-determinining region III (CDR III) of the immunoglobulin heavy chain genes showed identical gene rearrangements in the CLL- and the MM-cell population. Our findings prove a common clonal tumor origin of both B-cell diseases in this patient.

Curcumin in chronic lymphocytic leukemia——A review

Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Since the toxicity of conventional drugs exceeds the benefits of treating this leukemia type,patients are treated only in the advanced symptomatic stages.The current article reviews curcumin,its general actions and targets in cancer,and specifically that of it in chronic lymphocytic leukemia.

PURGING OF ACUTE NON-LYMPHOCYTIC LEUKEMIA PROGENITORS BY PROCAINE AND HYPERTHERMIA

Procaine and hyperthermia have been shown to possess a relatively selective cytotoxicity to leukemlc cells. In this study, the combined effects of procaine and hyperthermia on the growth of hematopoietic progenitors (GM-CFU) and ieukemic progenitors (L-CFU) were examined to determine if this combination resulted in a great selective killing of leukemlc cells than that achieved by procaine or heat alone. When the cells were treated simutaneously with procaine (2 mM) and hyperthermia (42℃) for one hour, the killing of L-CFU was enhanced considerably whereas GM-CFU were not markedly affected. These data Indicate that the combined treatment with procain and hyperthermia might offer an efficient mean to selectively purge residual leukemlc cells in vitro. Procaine with hyperthermia may have a role in clinical autoiogous bone marrow transplantation for acute leukemia.

Construction,Expression and in vitro Biological Effects of Idiotype Ig Fab Fragment of B-Chronic Lymphocytic Leukemia

The purpose of this study was to construct expression vectors of idiotype （Id） SmIg in patients with B-chronic lymphocytic leukemia and to express them in E.coli to obtain recombinant Id, and to investigate the effect of the protein on the proliferation and secretion of IL-2 and IFN-γ of stimulated peripheral blood mononuclear cells （PBMC） in vitro. Light chain gene and Fd fragment of heavy chain gene were inserted into fd-tet-DOG2 vector to construct fd-tet-DOG2-Fab. Fab gene was further cloned into expression vector pHEN2 to construct the soluble expression vector pHEN2-Fab. After induction by IPTG, Fab protein was purified by Ni-NTA-chromatography. MTT was used to determine the effects of purified protein on the proliferation of stimulated PBMC in vitro and the concentrations of IL-2 and IFN-γ in the culture supernatants were detected by ELISA. The results showed that recombinant pHEN2-Fab expression vector was constructed successfully. Fab protein was expressed in positive clone after induced by IPTG and two specific bands at 24-25 kD position were observed by SDS-PAGE electrophoresis. Proliferation of PBMC could be induced by purified Fab and the concentrations of IL-2 and IFN-γ in culture supernatants were increased significantly af- ter induction. It was suggested that the expression vector of SmIg Fab fragment was constructed suc- cessfully, and expressed and secreted from E. coli. The Fab protein could induce proliferation of PBMC and promote secretion of IL-2 and IFN-γ.

Disseminated infection by Fusarium solani in acute lymphocytic leukemia:A case report

BACKGROUND In recent years,the rate of immunosuppressed patients has increased rapidly.Invasive fungal infections usually occur in these patients,especially those who have had hematological malignances and received chemotherapy.Fusariosis is a rare pathogenic fungus,it can lead to severely invasive Fusarium infections.Along with the increased rate of immune compromised patients,the incidence of invasive Fusarium infections has also increased from the past few years.Early diagnosis and therapy are important to prevent further development to a more aggressive or disseminated infection.CASE SUMMARY We report a case of a 19-year-old male acute B-lymphocytic leukemia patient with fungal infection in the skin,eyeball,and knee joint during the course of chemotherapy.We performed skin biopsy,microbial cultivation,and molecular biological identification,and the pathogenic fungus was finally confirmed to be Fusarium solani.The patient was treated with oral 200 mg voriconazole twice daily intravenous administration of 100 mg liposomal amphotericin B once daily,and surgical debridement.Granulocyte colony-stimulating factor was administered to expedite neutrophil recovery.The disseminated Fusarium solani infection eventually resolved,and there was no recurrence at the 3 mo follow-up.CONCLUSION Our case illustrates the early detection and successful intervention of a systemic invasive Fusarium infection.These are important to prevent progression to a more aggressive infection.Disseminate Fusarium infection requires the systemic use of antifungal agents and immunotherapy.Localized infection likely benefits from surgical debridement and the use of topical antifungal agents.

INVESTIGATION OF INDUCING EFFECT OF SPECIFIC CYTOTOXICITY OF CTLS BY ANTIGEN PEPTIDES FROM T LYMPHOCYTIC LEUKEMIA CELLS

Objective: To investigate the characteristics of specific antitumor immunity induced by antigen peptides mixture from T lymphocytic leukemia cells. Method: Antigen peptides mixtures were prepared from different leukemia cell lines and then bound with Hsp70 in vitro. Human peripheral blood mononuclear cells (PBMC) were cultured in vitro, and activated with Hsp70-antigen peptides. The activated PBMC was cultured continuously in vitro, and used as effector cells in vitro test of cytotoxicity to different target cells. Results: The antigen peptides from different leukemia cell lines were peptides mixture and could activate PBMC effectively if they were presented by Hsp70. The activated PBMC could proliferate in the presence of IL-2 and Hsp70-antigen peptides. The proliferative PBMC had specific cytotoxicity to leukemia cells corresponding to the antigen peptides. PBMC activated by antigen peptides from T lymphocytic leukemia cell lines could effectively kill T lymphocytic leukemia cells, and the cytotoxicity of these PBMC to T lymphocytic leukemia cells was significantly stronger than that of PBMC activated by antigen peptides from other leukemia cells (P < 0.05). PBMC activated by either Hut78-peptides or Molt 4-peptides could effectively kill Jurkat cells. And the cytotoxicity of PBMC activated by Hut78/Molt-4-peptides to Jurkat cells was significantly stronger than that of PBMC activated by either Hut78-peptides or Molt-4-peptides alone (P<0.05). Conclusion: Antigen peptides mixture from T lymphocytic leukemia cell lines can induce specific cytotoxic effect to T lymphocytic leukemia cells. There exists cross-reactivity among antigen peptides mixture from different T lymphocytic leukemia cell lines. The cross-reactivity could be amplified by blending of different antigen peptides from different T lymphocytic leukemia cell lines, suggesting that it is possible to prepare broad-spectrum antigen peptide vaccine against T lymphocytic leukemia by using multiple leukemia cell lines.

Treatment for CD57-negativeγδT-cell large granular lymphocytic leukemia with pure red cell aplasia:A case report

BACKGROUND T-cell large granular lymphocytic leukemia(T-LGLL)is a rare type of aplastic anemia with diverse clinical manifestations.Concomitant diseases are often present at the first manifestation.We describe the treatment of a patient with CD57-negativeγδT-LGLL with pure red cell aplasia(PRCA).CASE SUMMARY A 34-year-old woman with a 20-year history of anemia visited our hospital owing to severe dizziness and was admitted.Her condition was diagnosed as CD57-negativeγδT-LGLL with PRCA through bone marrow cytology,bone marrow pathology,bone marrow flow cytometry,bone marrow multiplex polymerase chain reaction combined with fluorescent fragment analysis,and other tests.Treatment with prednisone,methotrexate,and subcutaneous erythropoietin did not significantly change her hemoglobin level.After treatment with oral cyclophosphamide for 3 mo,her hemoglobin level increased to approximately 100 g/L.After 5 mo of treatment,the patient could perform activities of daily living independently.CONCLUSION The treatment of CD57-negativeγδT-LGLL with PRCA with cyclophosphamide helps to improve prognosis.

Chronic lymphocytic leukemia/small lymphocytic lymphoma complicated with skin Langerhans cell sarcoma:A case report

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.

Massive ascites as a presenting manifestation of chronic lymphocytic leukemia

Ascites is not an uncommon manifestation of certain solid tumors like gastrointestinal malignancies, ovarian cancer and breast cancer. However, it is unusual to encounter ascites in patients with hematological malignancies especially chronic leukemia. The patient described here presented with massive ascites and blood lymphocytosis. Further studies confirmed the diagnosis of chronic lymphocytic leukemia with ascites. The ascitic fluid was exudative, consisting of mature-looking B-lymphocytes, which were morphologically and immunophenotypically similar to peripheral blood and bone marrow cells. The patient was treated with chemotherapy and achieved a good response and diminution of ascitic fluid accumulation.

A Rare Entity of Accelerated Chronic Lymphocytic Leukemia: A Report of Two Cases and Review of Literature

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.

Chronic Lymphocytic Leukemia of del 17p in a Young Subject: About a Case and Reviewed a Literature

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.

Mutation Analysis of IgVH Gene in B-Cell Chronic Lymphocytic Leukemia

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.

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

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.

A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation

Background:For patients with B cell acute lymphocytic leukemia(B-ALL)who underwent allogeneic stem cell transplantation(allo-SCT),many variables have been demonstrated to be associated with leukemia relapse.In this study,we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.Methods:A total of 477 patients with B-ALL who underwent allo-SCT at Peking University People’s Hospital from December 2010 to December 2015 were enrolled in this retrospective study.We aimed to evaluate the factors associated with transplant outcomes after allo-SCT,and establish a risk score to identify patients with different probabilities of relapse.The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables.Results:All patients achieved neutrophil engraftment,and 95.4%of patients achieved platelet engraftment.The 5-year cumulative incidence of relapse(CIR),overall survival(OS),leukemia-free survival(LFS),and non-relapse mortality were 20.7%,70.4%,65.6%,and 13.9%,respectively.Multivariate analysis showed that patients with positive post-transplantation minimal residual disease(MRD),transplanted beyond the first complete remission(≥CR2),and without chronic graft-versus-host disease(cGVHD)had higher CIR(P<0.001,P=0.004,and P<0.001,respectively)and worse LFS(P<0.001,P=0.017,and P<0.001,respectively),and OS(P<0.001,P=0.009,and P<0.001,respectively)than patients without MRD after transplantation,transplanted in CR1,and with cGVHD.A risk score for predicting relapse was formulated with the three above variables.The 5-year relapse rates were 6.3%,16.6%,55.9%,and 81.8%for patients with scores of 0,1,2,and 3(P<0.001),respectively,while the 5-year LFS and OS values decreased with increasing risk score.Conclusion:This new risk score system might stratify patients with different risks of relapse,which could guide treatment.

Chronic Lymphocytic Leukemia Prognostic Index： A New Inteorated Scorino System to Predict the Time to First Treatment in Chinese Patients with Chronic Lymphocytic Leukemia

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.

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

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.