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  1. Benner A, Mansouri L, Rossi D, Majid A, Willander K, Parker A, et al.
    Haematologica, 2014 Aug;99(8):1285-91.
    PMID: 25082786 DOI: 10.3324/haematol.2013.101170
    A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis*; Leukemia, Lymphocytic, Chronic, B-Cell/genetics*
  2. Azira NMS, Zeehaida M, Nazli Z, Suraiya S
    A 36-year-old man with underlying chronic lymphocytic leukemia had left arm swelling for a duration of 3 months. Clinically, the affected arm was swollen, erythematous and tender. Epicoccum nigrum was isolated from the culture of the tissue that was obtained intraoperatively. He was treated and responded to voriconazole therapy. To the best of our knowledge, this is the first case of intramuscular abscess as a result of E. nigrum infection in an immunocompromised patient.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
  3. Azira NMS, Zeehaida M, Nazli Z, Suraiya S
    MyJurnal
    A 36-year-old man with underlying chronic lymphocytic leukemia had left arm swelling for a duration of 3 months. Clinically, the affected arm was swollen, erythematous and tender. Epicoccum nigrum was isolated from the culture of the tissue that was obtained intraoperatively. He was treated and responded to voriconazole therapy. To the best of our knowledge, this is the first case of intramuscular abscess as a result of E. nigrum infection in an immunocompromised patient.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
  4. Chen SW, Chang ST, Hsieh YC, Kuo CC, Wu HC, Feng YH, et al.
    Malays J Pathol, 2020 Aug;42(2):237-243.
    PMID: 32860376
    INTRODUCTION: Follicular lymphoma (FL) is usually a nodal lymphoma expressing CD10, rarely with leukaemic presentation (FL-LP).

    MATERIALS AND METHODS: We searched for FL-LP in our institution from 2000 to 2018 and characterised the neoplastic cells by flow cytometry, immunohistochemistry and fluorescence in situ hybridization. Thirteen (6.1%) of 212 FL cases were FL-LP, all de novo neoplasms. The leukaemic cells were small in 12 cases and large in one. All had concurrent FL, mostly (92%; 12/13) low-grade. The single case with large leukaemic cells had a concurrent primary splenic low-grade FL and a double-hit large B-cell lymphoma in the marrow.

    RESULTS: CD10 was expressed in the leukaemic cells in 38% (5/13) cases by flow cytometry and in 77% (10/13) cases in tumours (p= 0.0471). IGH/BCL2 reciprocal translocation was identified in 85% (11/13) cases. Most patients were treated with chemotherapy. In a median follow-up time of 36 months, nine patients were in complete remission. The 2- and 5-year survival rates were at 100% and 83%, respectively. In this study, we characterised a series of de novo FL-LP in Taiwan. All patients had concurrent nodal and/or tissue tumours, which might suggest that these patients seek medical help too late.

    CONCLUSION: The lower CD10 expression rate by flow cytometry than by immunohistochemistry might be due to different epitopes for these assays. Alternatively, loss of CD10 expression might play a role in the pathogenesis of leukaemic change. The clinical course of FL-LP could be aggressive, but a significant proportion of the patients obtained complete remission with chemotherapy.

    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
  5. Basabaeen AA, Abdelgader EA, BaHashwan OS, Babekir EA, Abdelateif NM, Bamusa SA, et al.
    BMC Res Notes, 2019 May 23;12(1):282.
    PMID: 31122288 DOI: 10.1186/s13104-019-4319-8
    OBJECTIVE: To investigate the ZAP-70 and CD38 expressions and their combined expressions in Sudanese B-CLL patients and their relationships with clinical and hematological characteristics as well as the disease staging at presentation.

    RESULTS: In the present cross-sectional descriptive study, analysis of ZAP-70 expression showed that 36/110 (32.7%) patients positively expressed ZAP-70 and insignificant higher presentation in intermediate and at advanced stages as well as no correlation was seen with hematological parameters and clinical features compared with negatively ZAP-70, on the other hand, 41/110 (37.3%) were CD38+ and no significant correlation was shown with the stage at presentation, clinical characteristics (except Splenomegaly, P = 0.02) and hematological parameters. However, in combined expressions of both ZAP-70 and CD38 together, 20/110 (18.2%) were concordantly ZAP-70+/CD38+, 53/110 (48.2%) concordantly ZAP-70-/CD38- and 37/110 (33.6%) either ZAP-70+ or CD38+, and these three groups showed insignificant correlation with clinical (except Splenomegaly, P = 0.03) and hematological parameters, and the stage at presentation. Our data showed the combined analysis of these two markers, lead to classify our patients into three subgroups (either concordant positive, negative or discordant expressions) with statistically insignificant correlation with clinical presentation (except Splenomegaly), hematological parameters and stage at presentation of B-CLL patients.

    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis*; Leukemia, Lymphocytic, Chronic, B-Cell/genetics; Leukemia, Lymphocytic, Chronic, B-Cell/immunology; Leukemia, Lymphocytic, Chronic, B-Cell/pathology
  6. Mohamad A, Hassan R, Husin A, Johan MF, Sulong S
    Asian Pac J Cancer Prev, 2021 Jan 01;22(1):85-91.
    PMID: 33507683 DOI: 10.31557/APJCP.2021.22.1.85
    OBJECTIVE: Chronic Lymphocytic Leukemia (CLL) is a common leukemia among Caucasians but rare in Asians population. We postulated that aberrant methylation either hypermethylation or partial methylation might be one of the silencing mechanisms that inactivates the tumour suppressor genes in CLL. This study aimed to compare the methylation status of tumour suppressor gene, ADAM12, among CLL patients and normal individuals. We also evaluated the association between methylation of ADAM12 and clinical and demographic characteristics of the participants.

    METHODS: A total of 25 CLL patients and 25 normal individuals were recruited in this study. The methylation status of ADAM12 was determined using Methylation-Specific PCR (MSP); whereas, DNA sequencing method was applied for validation of the MSP results.

    RESULTS: Among CLL patients, 12 (48%) were partially methylated and 13 (52%) were unmethylated. Meanwhile, 5 (20%) and 20 (80.6%) of healthy individuals were partially methylated and unmethylated, respectively. There was a statistically significant association between the status of methylation at ADAM12 and the presence of CLL (p=0.037).

    CONCLUSION: The aberrant methylation of ADAM12 found in this study using MSP assay may provide new exposure to CLL that may improve the gaps involved in genetic epigenetic study in CLL.

    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/genetics; Leukemia, Lymphocytic, Chronic, B-Cell/pathology*
  7. Ainoon O, Hamidah AB, Cheong SK, Hamidah HN
    Malays J Pathol, 2000 Jun;22(1):5-11.
    PMID: 16329531
    Rearrangement of the immunoglobulin heavy chain (IgH) gene has been used as a marker of lineage and clonality in the diagnosis of B lymphoproliferative disorders. A number of PCR-based techniques have been developed to overcome the disadvantages of Southern blotting, the standard technique in detecting IgH gene rearrangement. Using an established seminested PCR technique with consensus primers to the V and J regions of the IgH gene, we analysed DNA prepared from peripheral blood and/or bone marrow specimens from 30 cases of known B cell malignancies (16 chronic lymphocytic leukemia, 11 acute lymphoblastic leukemia and 3 Non-Hodgkin Lymphoma), 3 cases of T lymphoproliferative disease and 3 cases of reactive lymphocytosis diagnosed in Hospital UKM to detect rearranged IgH gene. We found that monoclonality as represented by the presence of rearranged IgH gene were demonstrated in all the 30 cases. The PCR findings showed 100% concordance with the Southern blot analysis results which also showed rearranged IgH bands in all the 30 cases. We also found that none of the cases of T lymphoproliferative diseases and reactive lymphocytosis showed presence of rearranged IgH band, suggesting that the amplification using the IgH primers is lineage-specific. In conclusion, we find the PCR a useful method to detect IgH gene rearrangement in peripheral blood and bone marrow specimen. Since the PCR results are comparable to that of the Southern blotting in demonstrating B cell monoclonality and owing to its many advantages we feel that it can replace the Southern blot technique for the diagnosis of B cell malignancies.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/genetics*; Leukemia, Lymphocytic, Chronic, B-Cell/immunology; Leukemia, Lymphocytic, Chronic, B-Cell/pathology
  8. Mohammed Basabaeen AA, Abdelgader EA, Babekir EA, Abdelrahim SO, Eltayeb NH, Altayeb OA, et al.
    Asian Pac J Cancer Prev, 2019 May 25;20(5):1579-1585.
    PMID: 31128065
    Objective: This study aimed at exploring the association of TP53 72Arg/Pro polymorphism and Risk of Chronic
    Lymphocytic Leukemia and to assess the correlation between TP53 72Arg/Pro polymorphism and clinical parameter,
    hematological profile and some biological prognostic markers among Sudanese patients with chronic lymphocytic
    leukemia. Methods: A case-control study was conducted in Khartoum state, Sudan, during the period from April 2017 to
    April 2018, involved 110 B-CLL patients and 80 healthy volunteers as a control group. Physical examination, Complete
    Blood Count and Immunophenotype were performed in all patients to confirm the diagnosis. Clinical staging such as
    Rai and Binet were studied. CD38 and ZAP70 were performed by Flow Cytometry. Blood samples were collected from
    all participants; DNA was extracted by using ANALYTIKJENA Blood DNA Extraction Kit (Germany) and analyzed
    TP53 codon 72Arg/Pro Polymorphism by using AS-PCR. The statistical analysis was performed using SPSS version
    23.0 software (Chicago, IL, USA). Results: the Arg/Pro was the most frequent genotype in B-CLL patients(50%),
    followed by Arg/Arg (25.5%) and Pro/Pro (24.5%), whereas in healthy control group Arg/Pro was the most frequent
    (47.5%), followed by Arg/Arg (45%) and Pro/Pro (7.5%). Our data indicate a higher frequency of homozygous Pro/
    Pro in the B-CLL patients as compared to controls with an OR of 4.01 for the Pro/Pro genotype and lower frequency
    of Arg/Arg genotype in CLL patients as compared to controls with an OR of .42 for the Arg/Arg genotype. Also, the
    Pro allele showed higher risk than Arg allele (P value=0.000, OR 2.23, 95% CI=1.45-3.41). No significant association
    between gender, clinical staging systems (Rai, Binet), biological prognostic markers (CD38 expression or ZAP70
    expression), and TP53 codon 72Arg/Pro polymorphisms, except Arg/Arg genotype tended to be associated with younger
    age (P =0.04). Conclusion: Our data suggested that Pro/Pro genotype contribute to increased susceptibility to B-Chronic
    Lymphocytic Leukemia risk in our population tenfold higher than those had Arg/Arg genotype.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/genetics*
  9. Masir N, Jones M, Lee AM, Goff LK, Clear AJ, Lister A, et al.
    Histopathology, 2010 Apr;56(5):617-26.
    PMID: 20459572 DOI: 10.1111/j.1365-2559.2010.03524.x
    To investigate the relationship between Bcl-2 protein expression and cell proliferation at single-cell level in B-cell lymphomas using double-labelling techniques.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/metabolism; Leukemia, Lymphocytic, Chronic, B-Cell/pathology
  10. Szoltysek K, Ciardullo C, Zhou P, Walaszczyk A, Willmore E, Rand V, et al.
    Int J Mol Sci, 2020 Oct 16;21(20).
    PMID: 33081245 DOI: 10.3390/ijms21207663
    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western World and it is characterized by a marked degree of clinical heterogeneity. An impaired balance between pro- and anti-apoptotic stimuli determines chemorefractoriness and outcome. The low proliferation rate of CLL cells indicates that one of the primary mechanisms involved in disease development may be an apoptotic failure. Here, we study the clinical and functional significance of DRAK2, a novel stress response kinase that plays a critical role in apoptosis, T-cell biology, and B-cell activation in CLL. We have analyzed CLL patient samples and showed that low expression levels of DRAK2 were significantly associated with unfavorable outcome in our CLL cohort. DRAK2 expression levels showed a positive correlation with the expression of DAPK1, and TGFBR1. Consistent with clinical data, the downregulation of DRAK2 in MEC-1 CLL cells strongly increased cell viability and proliferation. Further, our transcriptome data from MEC-1 cells highlighted MAPK, NF-κB, and Akt and as critical signaling hubs upon DRAK2 knockdown. Taken together, our results indicate DRAK2 as a novel marker of CLL survival that plays key regulatory roles in CLL prognosis.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell/metabolism*; Leukemia, Lymphocytic, Chronic, B-Cell/pathology
  11. Teoh CS, Goh AS
    Case Rep Transplant, 2021;2021:8831125.
    PMID: 33552611 DOI: 10.1155/2021/8831125
    A middle-aged gentleman who was diagnosed with high-risk chronic lymphocytic leukaemia (CLL), Rai stage IV, Binet C with del(17p) and del(13q) underwent allogeneic haematopoeitic stem cell transplantation (allo-HSCT) from a human leukocyte antigen (HLA) identical sister. The patient developed extensive skin, oral, and liver chronic graft versus host disease (GVHD) required tacrolimus, mycophenolate mofetil (MMF), and prednisolone. At seventh month after allo-HSCT, the patient presented with systemic symptoms, right cervical lymphadenopathy, splenomegaly, marked pancytopaenia, and elevated lactate dehydrogenase (LDH). Bone marrow study, immunophenotyping (IP), chromosome analysis, and PET-CT scan confirmed relapsed CLL with no evidence of Richter's transformation or posttransplant lymphoproliferative disease (PTLD). Withdrawal of immunosuppressant (IS) worsened cutaneous and liver GVHD. Chemotherapy was not a suitable treatment option in view of immunodeficiency. The patient underwent extracorporeal photopheresis (ECP) therapy eventually for extensive chronic GVHD, and the IS were gradually tapered to the minimal effective dose. The relapsed CLL was treated successfully with oral venetoclax accessible via a compassionate drug program. This case highlights challenges in managing relapsed CLL and loss of graft-versus-leukaemia (GVL) effect despite extensive chronic GVHD. Venetoclax is an effective and well-tolerated oral novel agent for relapsed CLL after allo-HSCT.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
  12. Ang Pei-Shen, Rajesh Ramasamy, Noor Hamidah Hussin, Cheong Soon-Keng, Seow Heng-Fong, Maha Abdullah
    MyJurnal
    Introduction: The phenotype and genotype of cancer cells portray hallmarks of cancer which may
    have clinical value. Cancer cell lines are ideal models to study and confirm these characteristics. We
    previously established two subtracted cDNA libraries with differentially expressed genes from an
    acute myeloid leukaemia patient with poor prognosis (PP) and good prognosis (GP). Objective: To
    compare gene expression of the leukaemia associated genes with selected biological characteristics
    in leukaemia cell lines and normal controls. Methodology: Expression of 28 PP genes associated
    with early fetal/embryonic development, HOX-related genes, hematopoiesis and aerobic glycolysis/
    hypoxia genes and 36 GP genes involved in oxidative phosphorylation, protein synthesis, chromatin
    remodelling and cell motility were examined in B-lymphoid (BV173, Reh and RS4;11) and myeloid
    (HL-60, K562) leukaemia cell lines after 72h in culture as well as peripheral blood mononuclear cells
    from healthy controls (N=5) using semi-quantitative polymerase chain reaction (PCR) method. Cell
    cycle profiles were analysed on flow cytometry while MTT cytotoxicity assay was used to determine
    drug resistance to epirubicin. Results: Genes expressed significantly higher in B-lymphoid leukaemia
    cell lines compared to healthy controls were mostly of the GP library i.e. oxidative phosphorylation
    (3/10), protein synthesis (4/11), chromatin remodelling (3/3) and actin cytoskeleton genes (1/5). Only
    two genes with significant difference were from the PP library. Cancer associated genes, HSPA9 and
    PSPH (GP library) and BCAP31 (PP library) were significantly higher in the B-lymphoid leukemia cell
    lines. No significant difference was observed between myeloid cell lines and healthy controls. This
    may also be due heterogeneity of cell lines studied. PBMC from healthy controls were not in cell cycle.
    G2/M profiles and growth curves showed B-lymphoid cells just reaching plateau after 72 hour culture
    while myeloid cells were declining. IC50 values from cytotoxicity assay revealed myeloid cell lines had
    an average 13-fold higher drug resistance to epirubicin compared to B-lymphoid cell lines. Only CCL1,
    was expressed at least two-fold higher in myeloid compared to B-lymphoid cell lines. In contrast,
    MTRNR2, EEF1A1, PTMA, HLA-DR, C6orf115, PBX3, ENPP4, SELL, and IL3Ra were expressed
    more than 2-fold higher in B-lymphoid compared to myeloid cell lines studied here. Conclusion: Thus,
    B-lymphoid leukaemia cell lines here exhibited active, proliferating characteristics closer to GP genes.
    Higher expression of several genes in B-lymphoid compared to myeloid leukaemia cell lines may be
    useful markers to study biological differences including drug resistance between lineages.
    Matched MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
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