- Recurrent Cytogenetic Abnormalities in Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia. [Journal Article]
- MMMethods Mol Biol 2017; 1541:279-293
- Characteristic chromosomal translocations are found to be associated with subtypes of B-cell non-Hodgkin lymphoma (NHL), for example t(8;14)(q24;q32) and Burkitt lymphoma, t(14;18)(q32;q21) and folli...
Characteristic chromosomal translocations are found to be associated with subtypes of B-cell non-Hodgkin lymphoma (NHL), for example t(8;14)(q24;q32) and Burkitt lymphoma, t(14;18)(q32;q21) and follicular lymphoma, and t(11;14)(q13;q32) in mantle cell lymphoma. Only few recurrent cytogenetic aberrations have been identified in the T-cell NHL and the best known is the ALK gene translocation t(2;5)(p23;q35) in anaplastic large cell lymphoma. Since lymph node or other tissue is seldom submitted for conventional cytogenetics study, alternative approaches for translocation detection are polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH). FISH is more sensitive than PCR in the detection of lymphoma translocations since directly labeled large FISH probes that span the translocation breakpoints are used. Although the recurrent chromosomal abnormalities in NHL are not completely sensitive and specific for disease entities, unlike the scenario in acute leukemia, cytogenetic and molecular genetic study is commonly used to aid lymphoma diagnosis and classification. Currently, the main clinical utility is in the employment of interphase FISH panels to predict disease aggressiveness to guide therapy, for example identification of double-hit lymphoma, or in prognostication, for example risk-stratification in chronic lymphocytic leukemia. The recent application of high-throughput sequencing to NHL not only advances the understanding of disease pathogenesis and classification, but allows the discovery of new drug targets, such as BRAF gene inhibition in hairy cell leukemia. Coupled with the increasing availability of novel molecular targeted therapeutic agents, the hope for the future is to translate the genetics and genomics information to achieve personalized medicine in NHL.
- Herpes Simplex Infection Simulating Richter Transformation: A Series of Four Cases and Review of the Literature. [Journal Article]
- HHistopathology 2016 Dec 01
- CONCLUSIONS: Herpes simplex infection of lymph nodes in patients with CLL/SLL results in clinicopathologic and radiologic findings that may mimic RT. It is essential to refrain from misclassifying these cases as RT as patients can respond remarkably well to antiviral therapy. This article is protected by copyright. All rights reserved.
- Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. [Journal Article]
- CCClin Cancer Res 2016 Nov 30
- Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-ind...
Purpose The oncogenic miR-155 is upregulated in many human cancers and its expression is increased in more aggressive and therapy resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors. Experimental Design We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia and acute lymphoblastic leukemia. Results We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism, and demonstrate that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer. Conclusions Our findings support the existence of a miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.
- CD30 Expression Is Rare in Myeloid Leukemia Cutis: A Study of 55 Cases and Implications for Routine Diagnostic Algorithms. [Journal Article]
- AJAm J Dermatopathol 2016 Nov 22
- Expression of CD30 in blastoid cutaneous infiltrates typically signifies a CD30 lymphoproliferative disorder, often requiring minimal immunohistochemical workup, if clinically consonant. However, mye...
Expression of CD30 in blastoid cutaneous infiltrates typically signifies a CD30 lymphoproliferative disorder, often requiring minimal immunohistochemical workup, if clinically consonant. However, myeloid and other hematologic malignancies often express CD30. We retrospectively examined the prevalence of CD30 expression in 41 patients (median age 59) and 55 biopsies with the diagnosis of leukemia cutis (LC) to determine whether an extensive immunohistochemical workup is warranted in all large, round cell CD30 cutaneous infiltrates. Each patient had refractory or recurrent disease, the histologic presence of a large mononuclear cell infiltrate, and varied cytogenetics. CD30 mononuclear cells within the infiltrate ranged from rare to many in 22 biopsies (22/55). In 18 biopsies, CD30 cells were interpreted as lymphocytic based on morphology, strong cytoplasmic and Golgi staining for CD30, and negative CD34 and CD117 staining. One case showing 3+ staining of lymphocytes was identified as a posttransplant lymphoproliferative disorder. The second 3+ case was favored to represent a subset of CD30-positive acute myeloid leukemia. Three other cases with 1+ membranous and cytoplasmic staining were interpreted as myeloid leukemia. In conclusion, CD30 positivity in myeloid leukemia in the skin is rare and does not often exhibit the strong membranous (2+ or 3+) and/or Golgi staining seen in reactive lymphocytes. Acute myeloid leukemia or myeloid LC may occasionally show 1+ (and rarely 2-3+) cytoplasmic/membranous or nonspecific blush nuclear CD30 labeling. Strong diffuse staining for CD30 should prompt consideration of a reactive lymphoid/lymphoproliferative process, and, when the clinical likelihood of CD30 LC is low, may obviate the need for further immunohistochemistry.
- LMO2 promotes tumor cell invasion and metastasis in basal-type breast cancer by altering actin cytoskeleton remodeling. [Journal Article]
- OOncotarget 2016 Nov 17
- LMO2 is traditionally recognized as a pivotal transcriptional regulator during embryonic hematopoiesis and angionenesis, and its ectopic expression in T lymphocyte progenitors is closely correlated t...
LMO2 is traditionally recognized as a pivotal transcriptional regulator during embryonic hematopoiesis and angionenesis, and its ectopic expression in T lymphocyte progenitors is closely correlated to the onset of acute T lymphocytic leukemia. However, recently studies revealed complicated expression features and dual functions of LMO2 on tumor behaviors in a variety of cancer types, including breast cancers. Basal-type breast cancer is one of the breast cancer subtypes and a prognostically unfavorable subtype among all breast cancers. Herein we found that in basal-type breast cancer specifically, high LMO2 expression was positively correlated with lymph node metastases in patients, promoted tumor cell migration and invasion and increased distant metastasis in SCID mice. Moreover, the novel function of LMO2 was achieved by its predominantly cytoplasmic location and interaction with cofilin1, which is a critical regulator in actin cytoskeleton dynamics. These findings suggest a subtype-dependent role of LMO2 in breast cancers and the potential of LMO2 as a subtype-specific biomarker for clinical practice.
- Recent advances in engineered T cell therapies targeting B cell malignancies. [Journal Article]
- DMDiscov Med 2016; 22(121):215-220
- Immunotherapy using engineered autologous T cells has been attempted for decades, but clinical trials have only recently demonstrated efficacy. The combination of enhanced manufacturing techniques, h...
Immunotherapy using engineered autologous T cells has been attempted for decades, but clinical trials have only recently demonstrated efficacy. The combination of enhanced manufacturing techniques, highly efficient engineering, appropriate target selection and synthetic receptors with potent T cell activating domains has led to the development of highly-active cellular therapy products. B-cell malignancies have served as the paradigmatic diseases to initially evaluate and subsequently hone engineered T cells targeting cancer. Two engineered receptors, transgenic T cell receptors (tTCRs) and chimeric antigen receptors (CARs), have been explored clinically at several different institutions. The most profound success has been in pediatric and adult acute lymphoblastic leukemia, in which complete response rates after treatment with CD19-directed CAR T cells approach 90%. Success has been slightly less impressive in slower-growing diseases such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), and experience is much more limited in the plasma cell disease multiple myeloma. A great deal of investigation is underway to understand the differences in response rates observed, and enhance the efficacy of these therapies in B cell cancers. Here, we review landmark and recent clinical trials, as well as pre-clinical work that demonstrates significant promise in propelling this field further in the coming years.
- Acute myeloid leukemia in Baraitser-Winter cerebrofrontofacial syndrome. [Journal Article]
- AJAm J Med Genet A 2016 Nov 21
- Baraitser-Winter malformation syndrome (BWMS), Fryns-Aftimos syndrome (FA), and craniofrontofacial syndromes (CFFs) have all been recently proposed to be part of the same phenotypic spectrum of Barai...
Baraitser-Winter malformation syndrome (BWMS), Fryns-Aftimos syndrome (FA), and craniofrontofacial syndromes (CFFs) have all been recently proposed to be part of the same phenotypic spectrum of Baraitser-Winter cerebrofrontofacial syndrome (BWCFF), which is characterized by facial dysmorphism, ocular coloboma, brain malformations, and intellectual disabilities. In addition to that, the recent discovery of missense mutations in one of the two ubiquitously expressed cytoplasmic β- and γ-acting-encoding genes ACTB (7p22.1) and ACTG1 (17q25.3) in patients carrying a clinical diagnosis of BWSM, FA, or CCF has provided further evidence that these clinical conditions do indeed belong to the same entity at the molecular level. Two cases of BWCFF patients presenting with malignancies (i.e., acute lymphocytic leukemia and cutaneous lymphoma) have been published thus far. Here, we report a 21-year-old female with molecularly confirmed FA, who developed acute myeloid leukemia (AML). The present finding may indicate that actinopathies could be cancer-predisposing syndromes although small numbers and publication bias should be taken into account. © 2016 Wiley Periodicals, Inc.
- Gallic Acid Inhibits Proliferation and Induces Apoptosis in Lymphoblastic Leukemia Cell Line (C121). [Journal Article]
- IJIran J Med Sci 2016; 41(6):525-530
- Leukemia is known as the world's fifth most prevalent cancer. New cytotoxic drugs have created considerable progress in the treatment, but side effects are still the important cause of mortality. Pla...
Leukemia is known as the world's fifth most prevalent cancer. New cytotoxic drugs have created considerable progress in the treatment, but side effects are still the important cause of mortality. Plant derivatives have been recently considered as important sources for the treatment of various diseases, including cancer. Gallic acid (GA) is a polyhydroxyphenolic compound with a wide range of biological functions. The aim of the present study was to evaluate the effect of GA on proliferation inhibition and apoptosis induction of a lymphoblastic leukemia cell line. Jurkat cell (C121) line was cultured in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum (FBS) with different concentrations of GA (10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 μM) for 24, 48 and 72 hours. The effect of GA on cell viability was measured using MTS assay. Induction of apoptosis was evaluated with Annexin V-FITC/PI kit and flow cytometry. Data were analyzed by SPSS version 20 using Kruskal-Wallis and Dunn's multiple comparison tests. Decline of cell viability to less than 50% was observed at 60.3±1.6, 50.9±1.5, and 30.9±2.8 μM concentration after 24, 48, and 72 hours incubation, respectively. All concentrations of GA (10, 30, 50 and 80 μM) enhanced apoptosis compared to the control (P<0.05). The results demonstrate that the polyphenolic compound, GA, is effective in inhibition of proliferation and induction of apoptosis in Jurkat cell line. It is recommended to study the mechanism of apoptosis induction in future investigations.
- Therapy-related acute myeloid leukemia following treatment of lymphoid malignancies. [Journal Article]
- OOncotarget 2016 Nov 10
- Therapy-related acute myeloid leukemia (t-AML) is a heterogeneous entity most frequently related to breast cancer or lymphoproliferative diseases (LD). Population-based studies have reported an incre...
Therapy-related acute myeloid leukemia (t-AML) is a heterogeneous entity most frequently related to breast cancer or lymphoproliferative diseases (LD). Population-based studies have reported an increased risk of t-AML after treatment of lymphomas. The aim of this study was to describe the characteristics and outcome of 80 consecutive cases of t-AML following treatment of LD. t-AML accounted for 2.3% of all AML cases, occurred 60 months after LD diagnosis, and were characterized by a high frequency of FAB M6 AML and poor-risk cytogenetic abnormalities. Time to t-AML diagnosis was influenced by patient age, type of LD, and treatment. Among the 48 t-AML patients treated with intensive chemotherapy, median overall survival (OS) was 7.7 months compared to 26.1 months in de novo, 4.2 months in post-myeloproliferative neoplasm, 9.4 months in post-myelodysplastic syndrome, 8.6 months in post-chronic myelomonocytic leukemia AML, 13.4 months in t-AML secondary to the treatment of solid cancer, and 14.7 months in breast cancer only. OS of post-LD t-AML patients was significantly influenced by age, performance status, myelodysplastic syndrome prior to LD/t-AML, and treatment regimen for LD. Thus, t-AML following lymphoid malignancies treatment should be considered as very high-risk secondary AML. New treatment strategies in patients with LD/t-AML are needed urgently.
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- Senescent stromal cell-induced divergence and therapeutic resistance in T cell acute lymphoblastic leukemia/lymphoma. [Journal Article]
- OOncotarget 2016 Nov 7
- T cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/LBL) is a precursor T cell leukemia/lymphoma that represents approximately 15% of all childhood and 25% of adult acute lymphoblastic leukemia. Alth...
T cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/LBL) is a precursor T cell leukemia/lymphoma that represents approximately 15% of all childhood and 25% of adult acute lymphoblastic leukemia. Although a high cure rate is observed in children, therapy resistance is often observed in adults and mechanisms leading to this resistance remain elusive. Utilizing public gene expression datasets, a fibrotic signature was detected in T-LBL but not T-ALL biopsies. Further, using a T-ALL cell line, CCRF-CEM (CEM) cells, we show that CEM cells induce pulmonary remodeling in immunocompromised mice, suggesting potential interaction between these cells and lung fibroblasts. Co-culture studies suggested that fibroblasts-induced phenotypic and genotypic divergence in co-cultured CEM cells leading to diminished therapeutic responses in vitro. Senescent rather than proliferating stromal cells induced these effects in CEM cells, due, in part, to the enhanced production of oxidative radicals and exosomes containing miRNAs targeting BRCA1 and components of the Mismatch Repair pathway (MMR). Collectively, our studies demonstrate that there may be bidirectional interaction between leukemic cells and stroma, where leukemic cells induce stromal development in vivo and senescent stromal cells generates genomic alterations in the leukemic cells rendering them therapeutic resistant. Thus, targeting senescent stroma might prove beneficial in T-ALL/LBL patients.