Danmei Xu

C-MYC Aberrations as Prognostic Factors in Diffuse Large B-cell Lymphoma: A Meta-Analysis of Epidemiological Studies

Objectives Various studies have investigated the prognostic value of C-MYC aberrations in diffuse large B-cell lymphoma (DLBCL). However, the role of C-MYC as an independent prognostic factor in clinical practice remains controversial. A systematic review and meta-analysis were performed to clarify the clinical significance of C-MYC aberrations in DLBCL patients. Methods The pooled hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS) were calculated as the main effect size estimates. The procedure was conducted according to the Cochrane handbook and PRISMA guidelines, including the use of a heterogeneity test, publication bias assessment, and meta-regression, as well as subgroup analyses. Results Twenty-four eligible studies enrolling 4662 patients were included in this meta-analysis. According to the nature of C-MYC aberrations (gene, protein, and mRNA), studies were divided into several subgroups. For DLBCL patients with C-MYC gene abnormalities, the combined HR was 2.22 (95% confidence interval, 1.89 to 2.61) for OS and 2.29 (95% confidence interval, 1.81 to 2.90) for EFS, compared to patients without C-MYC gene abnormalities. For DLBCL patients with overexpression of C-MYC protein and C-MYC mRNA, pooled HRs for OS were 2.13 and 1.62, respectively. C-MYC aberrations appeared to play an independent role among other well-known prognostic factors in DLBCL. Addition of rituximab could not overcome the inferior prognosis conferred by C-MYC. Conclusion The present systematic review and meta-analysis confirm the prognostic value of C-MYC aberrations. Screening of C-MYC should have definite prognostic meaning for DLBCL stratification, thus guaranteeing a more tailored therapy.

Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation

Although dramatic clinical success has been achieved in acute promyelocytic leukemia (APL), the success of differentiating agents has not been reproduced in non-APL leukemia. A key barrier to the clinical success of arsenic is that it is not potent enough to achieve a clinical benefit at physiologically tolerable concentrations by targeting the leukemia cell differentiation pathway alone. We explored a novel combination approach to enhance the eradication of leukemia stem cells (LSCs) by arsenic in non-APL leukemia. In the present study, phosphatidylinositol 3-kinase /AKT/mammalian target of rapamycin (mTOR) phosphorylation was strengthened after As(2)S(2) exposure in leukemia cell lines and stem/progenitor cells, but not in cord blood mononuclear cells (CBMCs). propidium iodide-103, the dual PI3K/mTOR inhibitor, effectively inhibited the transient activation of the PI3K/AKT/mTOR pathway by As(2)S(2). The synergistic killing and differentiation induction effects on non-APL leukemia cells were examined both in vitro and in vivo. Eradication of non-APL LSCs was determined using the nonobese diabetic/severe combined immunodeficiency mouse model. We found that a combined As(2)S(2)/PI-103 treatment synergized strongly to kill non-APL leukemia cells and promote their differentiation in vitro. Furthermore, the combined As(2)S(2)/PI-103 treatment effectively reduced leukemia cell repopulation and eradicated non-APL LSCs partially via induction of differentiation while sparing normal hematopoietic stem cells. Taken together, these findings suggest that induction of the PI3K/AKT/mTOR pathway could provide a protective response to offset the antitumor efficacy of As(2)S(2). Targeting the PI3K/AKT/mTOR pathway in combination with As(2)S(2) could be exploited as a novel strategy to enhance the differentiation and killing of non-APL LSCs.

Abnormal immunophenotype provides a key diagnostic marker: a report of 29 cases of de novo aggressive natural killer cell leukemia

Aggressive natural killer (NK) cell leukemia (ANKL) is a systemic neoplastic proliferation of NK cells with an aggressive clinical course. Currently, the diagnosis of ANKL remains challenging. In the current study, we report the clinical, laboratory, immunophenotypic, and genetic findings from 29 cases of de novo ANKL in a single center and evaluate the relative contribution of these features to the diagnosis of ANKL. Clinical features, laboratory findings, morphologic, cytogenetic features, and Epstein-Barr virus status were important factors for diagnosing aggressive NK cell leukemia. On the other hand, ANKL displays a strikingly abnormal immunophenotype in contrast to nonneoplastic NK cells. The immunophenotype of ANKL cells may differ from reactive NK cells in 4 respects. First, the CD45/linear side scatter gating of flow cytometry allows the initial identification of neoplastic subpopulations for additional immunophenotypic analysis in half of ANKL cases. Second, unusual expression of surface antigens in ANKL cells was a prominent feature. Third, the clonality of ANKL cells could be identified using antibodies against CD158a/h, CD158b, or CD158e. Last, the positive rate of Ki-67 expression in ANKL cells was generally high. Based on these findings, we provide an objective marker based on clinical data for the definite diagnosis of ANKL.

Successful engraftment of human acute lymphoblastic leukemia cells in NOD/SCID mice via intrasplenic inoculation

Acute lymphoblastic leukemia (ALL) is a heterogeneous disorder, and primary drug resistance and relapse are thought to be the main causes for treatment failure in ALL patients. For these refractory or relapsed patients, there is an increasing demand to identify novel therapeutic approaches, which will highly rely on the use of xenotransplantation models in translational research. Given the critical role that the spleen plays in the hematopoiesis and lymphopoiesis in adult mice, intrasplenic inoculation of ALL cells into immunodeficient mice may represent a feasible route for leukemic xenotransplantation. In the present study, engraftments via intrasplenic inoculation in anti-mCD122 mAb conditioned NOD/SCID mice were achieved in 5 out of 11 cases, and the engrafted cells reconstituted a complete leukemic phenotype. The engrafted cells sustained the self-renewal capacity of leukemia-initiating cells as tested by serial xenotransplantation and can be used for evaluation of antileukemic drugs. These data suggest that the combination of intrasplenic inoculation and the targeted depletion of CD122+ cells could provide a novel approach for the xenotransplantation of ALL cells in NOD/SCID mice. Furthermore, this model can be used for stem cell research, long-term analysis of engraftment kinetics and in vivo drug tests.

SIL-TAL1 rearrangement is related with poor outcome: a study from a Chinese institution.

SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL), however its prognostic implication remains controversial. To investigate the clinical characteristics and outcome of this subtype in Chinese population, we systemically reviewed 62 patients with newly diagnosed T-ALL, including 15 patients with SIL-TAL1 rearrangement. We found that SIL-TAL1+ T-ALL was characterized by higher white blood cell count (P = 0.029) at diagnosis, predominant cortical T-ALL immunophenotype (P = 0.028) of the leukemic blasts, and a higher prevalence of tumor lysis syndrome (TLS, P<0.001) and disseminated intravascular coagulation (DIC, P<0.001), which led to a higher early mortality (P = 0.011). Compared with SIL-TAL1− patients, SIL-TAL1+ patients had shorter relapse free survival (P = 0.007) and overall survival (P = 0.002). Our NOD/SCID xenotransplantation model also demonstrated that SIL-TAL1+ mice models had earlier disease onset, higher leukemia cell load in peripheral blood and shorter overall survival (P<0.001). Moreover, the SIL-TAL1+ mice models exerted a tendency of TLS/DIC and seemed vulnerable towards chemotherapy, which further simulated our clinical settings. These data demonstrate that SIL-TAL1 rearrangement identifies a distinct subtype with inferior outcome which could allow for individual therapeutic stratification for T-ALL patients.

Aggressive Natural Killer Cell Leukemia Secondary to HodgkinLymphoma: a Case Report and Review of the Literature

A 32-year old Chinese woman presented with high fever (39C), lymphadenopathy, hepatosplenomegaly, shortness of breath and general fatigue after initial remission of Hodgkin lymphoma (HL). The immuno-phenotype of blast cells found in her peripheral blood and pleural fluid suggested abnormal Natural Killer (NK) cells (CD2+CD3- CD56+CD45RO+HLADR+CD94+ with high Ki67). Her serum EB virus DNA was over 1.0×107IU/mL. Combining her clinical symptom and laboratory data, the patient was diagnosed with Hodgkin Lymphoma, secondary NK cell leukemia and haemophagocytic lymphohistocytosis (HLH). To date, this is the first reported case that developed secondary ANKL after the treatment of Hodgkin Lymphoma. Secondary treatment-related cancers are a major problem in HL survivors. Thus, novel treatment strategies for HL should aim at a reduction of chemotherapy and radiation therapy in order to reduce the risk for development of therapy-related malignancies. In conclusion, improvements of combined therapy as well as close monitoring during clinical follow up could warrant the improved overall survival of HL and prevent fatal complications.

Inhibition of STAT3 activity re-activates anti-tumor immunity but fails to restore the immunogenicity of tumor cells in a B-cell lymphoma model

A large number of patients with advanced lymphoma become refractory or relapse after initial treatment due to the persistence of minimal residual disease. Ideal immunotherapy strategy for eradicating the minimal residual disease of lymphoma and preventing the tendency to relapse need to be developed. Here, we use a mice model mimicked the disease entities of aggressive B-cell lymphoma dynamically to analyze the host anti-lymphoma immunity during the progression of lymphoma. We have shown that STAT3 activity was gradually enhanced in host immune effector cells with the progression of lymphoma. Inhibition of the STAT3 activity with a small molecule inhibitor was able to effectively enhance the function of both host innate and adaptive immunity, and thereby delayed the progression of lymphoma. Despite the therapeutic benefits were achieved by using of the STAT3 inhibitor, disrupting of STAT3 pathway did not prevent the eventual development of lymphoma due to the presence of point mutation of β2M, which controls immune recognition by T cells. Our findings highlight the complexity of the mechanism of immune evasion; therefore a detailed analysis of genes involved in the immune recognition process should be essential before an elegant immunotherapy strategy could be conducted.