T-cell Lymphoblastic Lymphoma Research Articles

Downregulation of specific FBXW7 isoforms with differential effects in T-cell lymphoblastic lymphoma.

FBXW7 is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, β and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7 in a panel of primary T-cell lymphoblastic lymphomas characterised by the absence of mutations in its sequence. We observed that decreased expression mainly affected the FBXW7β isoform and to a lesser extent FBXW7α and may be attributed to the combined effect of epigenetic changes, alteration of upstream factors and upregulation of miRNAs. Transient transfections with miRNA mimics in selected cell lines resulted in a significant decrease of total FBXW7 expression and its different isoforms separately, with the consequent increment of critical substrates and the stimulation of cell proliferation. Transient inhibition of endogenous miRNAs in a T-cell lymphoblastic-derived cell line (SUP-T1) was capable of reversing these proliferative effects. Finally, we show how FBXW7 isoforms display different roles within the cell. Simultaneous downregulation of the α and γ isoforms modulates the amount of CCNE1, whilst the β-isoform alone was found to have a prominent role in modulating the amount of c-MYC. Our data also revealed that downregulation of all isoforms is a sine qua non condition to induce a proliferative pattern in our cell model system. Taking these data into account, potential new treatments to reverse downregulation of all or a specific FBXW7 isoform may be an effective strategy to counteract the proliferative capacity of these tumour cells.

Outcome and survival in children with Non-Hodgkin’s lymphoma

Background Non-Hodgkin lymphoma is the third most common malignant tumor in children. It includes four major subtypes: Burkitt Lymphoma (BL), Lymphoblastic Lymphoma (LL), Diffuse Large B-cell Lymphoma (DLBL) and Anaplastic Large Cell Lymphoma (ALCL). The use of multidrug chemotherapy, radiation therapy, biologic agents, and improved diagnostic and supportive care resulted in better cure rates. Objective This study is to report prognosis and outcome of Non-Hodgkin lymphoma (NHL) patients at tertiary health care facility in King Faisal Specialist Hospital and Research Center, Jeddah (KFSHRC-J). Materials and Method A retrospective cross-sectional study of all eligible patients with Non-Hodgkin lymphoma (NHL), admitted, diagnosed and managed at King Faisal Specialist Hospital and Research Center, Jeddah from Jan 2005 to December 2016, previously untreated, with biopsy proven NHL and Age ≤ 15 years at diagnosis. Clinical data Research Form used to collect patient’s data from medical records. Demographic, Clinical and Survival data analysed using Statistical Package for Social Sciences. Results Thirty-one pediatric patients with biopsy proven Non-Hodgkin lymphoma (NHL) fulfilled the inclusion criteria. Twenty-six (80.6%) were males. Nineteen (61.3%) patients were ≤ 10 years of age at diagnosis, while 12 (38.7%) were>10 years of age. The mean age at diagnosis was 8.1years. The commonest primary site is abdomen (n=19, 61.3%), followed by Head & Neck (n=9, 28.1%), mediastinum (n=1, 3.1%), primary CNS (n=1, 3.1%), bone (n=1, 3.1%) and skin (n=1, 3.1%). Regarding histology 19 (61.3%) had Burkitt Lymphoma (BL), 6 (19.4%) had Diffuse Large B-cell Lymphoma (DLBL), 2(6.4%) had T-cell Lymphoblastic Lymphoma, 2 (6.4%) had T-cell rich B Cell Lymphoma, 1 (3.1%) had B-cell Lymphoma not otherwise specified and 1 (3.1%) had Cutaneous Anaplastic Large Cell Lymphoma (ALCL). Predominantly, patients presented in advanced stages III (n=18, 60%) and IV (n=10, 33%).Twenty-five (77.8%) patients completed treatment and are well to date while six of the patients (18.6%) died during the study period. Conclusion Children admitted to the (KFSHRC-J) appeared affected by non-Hodgkin Lymphoma at a younger age, with a higher incidence of Burkitt's Lymphoma. The predominant presenting site is abdomen followed by head/neck. They present mostly with advance disease. Survival rates are similar to those described in the literature of developed countries.

Non-leukemic pediatric mixed phenotype acute leukemia/lymphoma: Genomic characterization and clinical outcome in a prospective trial for pediatric lymphoblastic lymphoma.

Rare cases of hematological precursor neoplasms fulfill the diagnostic criteria of mixed phenotype acute leukemia (MPAL), characterized by expression patterns of at least two hematopoietic lineages, for which a highly aggressive behavior was reported. We present a series of 11 pediatric non-leukemic MPAL identified among 146 precursor lymphoblastic lymphomas included in the prospective trial Euro-LBL 02. Paraffin-embedded biopsies of 10 cases were suitable for molecular analyses using OncoScan assay (n = 7), fluorescence in situ hybridization (FISH; n = 7) or both (n = 5). Except for one case with biallelic KMT2A (MLL) breaks, all cases analyzed by FISH lacked the most common translocations defining molecular subsets of lymphoblastic leukemia/lymphomas. Two non-leukemic B-myeloid MPALs showed the typical genomic profile of hyperdiploid precursor B-cell lymphoblastic leukemia with gains of chromosomes 4, 6, 10, 14, 18, and 21. One B-T MPAL showed typical aberrations of T-cell lymphoblastic lymphoma, such as copy number neutral loss of heterozygosity (CNN-LOH) at 9p targeting a 9p21.3 deletion of CDKN2A and 11q12.2-qter affecting the ATM gene. ATM was also mutated in a T-myeloid MPAL case with additional loss at 7q21.2-q36.3 and mutation of NRAS, two alterations common in myeloid disorders. No recurrent regions of CNN-LOH were observed. The outcome under treatment was good with all patients being alive in first complete remission after treatment according to a protocol for precursor lymphoblastic lymphoma (follow-up 3-10 years, median: 4.9 years). In summary, the present series of non-leukemic MPALs widely lacked recurrently reported translocations in lymphoid/myeloid neoplasias and showed heterogeneous spectrum of chromosomal imbalances.

MEG3 affects the progression and chemoresistance of T-cell lymphoblastic lymphoma by suppressing epithelial-mesenchymal transition via the PI3K/mTOR pathway.

Long noncoding RNAs (lncRNA) are emerging as integral functional and regulatory components in the development of different diseases including cancer. Maternally expressed gene 3 (MEG3), is a lncRNA, that has a depressed expression in multiple tumor types, including T-cell lymphoblastic lymphoma (T-LBL). However, the molecular mechanisms that regulate the tumorigenic functions of MEG3 in T-LBL remain largely unknown. In this study, we aimed to discover and identify the function of MEG3 in T-LBL tumorigenesis, epithelial-mesenchymal transition (EMT) and drug resistance, and explore their mechanisms of action. Knockdown MEG3 promoted the proliferation, migration, invasion, and drug resistance of T-LBL cells while overexpression of MEG3 gets the opposite results. The mechanism study showed that decreased MEG3 expression in T-LBL cells could activate PI3K/mTOR signaling pathways, increase the expression of p-glycoprotein and affect the expression of EMT markers for transforming to mesenchymal cells in vitro and in vivo. Together, these results indicate that MEG3 could inhibit the migration, invasion, and drug resistance in T-LBL cells by suppression of the PI3K/mTOR pathway. MEG3 might be a potential target, through which poor prognosis with high recurrence and drug resistance of T-LBL in a clinical setting could be reversed.

GSK458 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in T Cell Lymphomas As a Single Agent and in Combination Therapy

Introduction: T-cell lymphoma (TCL) accounts approximately 15% of all Non-Hodgkin's lymphoma cases. TCL are often divided into either systemic or cutaneous TCL (CTCL). The management of TCL systemic or cutaneous is challenging because the emergence of chemotherapy resistance that lead to early death (systemic T-cell lymphomas) or chronic debilitating clinical course (CTCL). To improve the clinical outcomes and reduce treatment-related toxicity, research need to be done focusing on understanding and targeting the molecular mechanism driving TCL subtypes. Recently, studies showed that the PI3K AKT/mTOR pathway was activated in TCL. GSK458 is a potent oral dual inhibitor of pan PI3K (α, β, γ and δ) and mTOR (mTOR1 and mTOR2). Preclinical studies in B-cell lymphomas showed GSK458 had broad antitumor activity in vitro and in vivo. In 2016, Phase I clinical trial of GSK458 was competed at the maximal dosage of 2.5mg twice daily. However, the effects of GSK458 on T-cell malignancies remain utterly unknown. Here, we evaluated the activity of GSK458 in preclinical T cell lymphoma models. Methods: We used a panel of T-cell lymphoma cell lines representing PTCL (J45), T-cell lymphoblastic lymphoma (SupT-1), and Mycosis Fungoides (MF)(MJ, HH and H9). TCL cell lines were exposed to escalating doses of GSK458 (1nM-100µM) without or with chemotherapeutic agents (doxorubicin, cisplatin, carboplatin, and dexamethasone); Bcl-2 inhibitor (Venetoclax); proteasome inhibitors ( bortezomib, carfilzomib, Ixazomib); or HDAC inhibitors (SAHA) for 48 and 72 hrs. Differences in cell viability, ATP levels, low mitochondria potential, glucose update, apoptosis and cell cycle distribution were evaluated utilizing PrestoBlue, Cell-Titer Glo assays, DiOC6, 2-NDG, Annexin V and propidium iodide staining followed by flow cytometric analysis, respectively. IC50 was calculated by GraphPad. PI3K and mTOR downstream pathway phosphorylation status, such as p-AKT Ser473, p-AKT Thr308, p-mTOR and p-GSK3β were detected by internally staining of FITC conjugated-antibodies followed by flow cytometry. Apoptosis proteins (MCL-1, PARP, p53, XIAP etc.) were detected by western blot. The additive/synergistic activity of GSK458 was detected by presto blue assay and Coefficient of synergy was calculated using CalcuSyn. Results:In vitro exposure of TCL cell lines to GSK458 demonstrated a dose- and time-dependent cell death. The IC50 of the cells were ranged from 3nM to 1.05uM at 72 hours. At 72h, GSK458 10nM lowered cellular mitochondrial potential, ATP levels and glucose uptake. GSK458 induced apoptosis and arrested the cell cycle at G1. At molecular level, GSK458 reduced phosphorylation status of AKT ser473 and Thr308, mTOR and GSK3β. Interestingly, GSK458 inhibited Mcl-1 expression level. GSK458 exhibited synergistic activity when combined with doxorubicin and dexamethasone. To a lesser degree, GSK458 enhanced the anti-tumor activity of Venetoclax, proteasome and HDAc inhibitors. Conclusion: GSK458 is active as a single agent or in combination with chemotherapy agents or small molecule inhibitors in a variety of T-cell pre-clinical models representing forms of systemic or cutaneous T-cell lymphoma. GSK458 was able to inhibit phosphorylation of AKT, mTOR and GSK3β, which may be the mechanism to reduce ATP production and glucose uptake in the cancer cells. Moreover, GSK458 arrested cell cycle at G1 arrest. Our data supports the clinical evaluation of GSK458 in relapsed/refractory T-cell lymphoma patients. (Supported by Roswell Park Cancer Institute Alliance Foundation Grant) DisclosuresNo relevant conflicts of interest to declare.

Tandem Autologous Hematopoietic Stem Cell Transplantation Treatment for Adult T-Cell Lymphoblastic Lymphoma: A Multiple Center Prospective Study in Southwestern China

BackgroudT-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive lymphoma with very poor clinical outcomes which has not standard treatment. This study evaluated the efficacy and safety of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) treatment for adult T-LBL and assessed the factors that affect survival.Methods160 newly diagnosed adult T-LBL patients were divided into three groups: chemotherapy group (68 patients), single auto-HSCT group (46 patients), and tandem auto-HSCT group (46 patients). The primary outcome measure was failure-free survival. The intermediate primary outcomes were progression/relapse rate and overall survival. Factors influencing toxicity related to tandem auto-HSCT treatment and prognosis for the patients were analyzed as well.ResultsThe 3-year progression/relapse rate of the tandem auto-HSCT group was significantly lower than that of the single auto-HSCT group and chemotherapy group (19.6% vs 45.7% and 70.6%, p < 0.05). The 3-year PFS rate and OS rate of the tandem auto-HSCT group (68.3% and 72.5%, respectively) were significantly higher than those of the single auto-HSCT group (41.5% and 55.4%, respectively, p < 0.05) and the chemotherapy group (23.3% and 43.3%, respectively, p < 0.05). In the tandem auto-HSCT group, age and disease status after the first transplant had an influence on the OS and PFS. Multivariate analysis identified disease status after the first transplant as the only independent prognostic factor for outcome in T-LBL.ConclusionsTandem auto-HSCT improves long-term survival of adult T-LBL patients. Disease status after the first transplant was an independent prognostic indicator for those patients. DisclosuresNo relevant conflicts of interest to declare.

Histopathological and immunophenotypical assessment of canine primary splenic lymphoma according to the World Health Organization

ABSTRACT: Although there are several studies addressing multicentric lymphoma in dogs, data regarding splenic lymphoma remains scarce. The diagnosis of splenic lymphoma using the World Health Organization (WHO) classification system can aid prognostic characterization of splenic lymphoma. The aim of this study was to evaluate the most common histological types of splenic lymphoma in dogs from Brazil according to the WHO classification. We assessed 33 cases of splenic lymphoma diagnosed by histopathologic and immunohistochemical (IHC) analysis submitted to VETPAT- Pathology Laboratory, Campinas-SP, Brazil. IHC was performed using antibodies against CD3 for T-cell and CD79α for B-cell identification . Mean age of patients with splenic lymphoma was 9.8 years. The most affected breeds were mixed breed dogs (33%) followed by Pit bulls and Yorkshires (9.0%). The most prevalent histological type was marginal zone B-cell lymphoma (60.7%) followed by diffuse large B-cell lymphoma (12.1%) and lymphoblastic T-cell lymphoma (12.1%). Histological and immunohistochemical characterization of splenic lymphoma is important due to the high prevalence of indolent lymphomas such as marginal zone, which may be less aggressive and thus have different prognostic and distinct forms of treatment when compared to high-grade lymphomas.

Cryptic NUP214-ABL1 fusion with complex karyotype, episomes and intra-tumor genetic heterogeneity in a T-cell lymphoblastic lymphoma

The Journal of Cancer Metastasis and Treatment is an open access journal focused on cancer metastasis and treatment, including the occurrence, development, progression, metastasis, and treatment of oncologic disease. It covers basic, translational and clinical research related to cancer cell biology, genomics, precision medicine, oncology internal medicine, radiotherapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neurooncology, etc.

Positron emission tomography/computed tomography as a clinical diagnostic tool for anterior mediastinal tumors.

The purpose of this study was to assess the usefulness of positron emission tomography/computed tomography (PET/CT) in the differential diagnosis of anterior mediastinal tumors. A total of 94 patients with anterior mediastinal masses or nodules (male, n = 41; female, n = 53; age, 17-84years) were retrospectively evaluated. All patients were evaluated by PET/CT and the masses or nodules were histologically diagnosed in our institution. Anterior mediastinal masses and nodules were classified into two disease categories: Low (thymic hyperplasia, thymoma, mature teratoma, and MALT lymphoma) and High (thymic carcinoid, thymic cancer, diffuse large B-cell lymphoma, T-cell lymphoblastic lymphoma, Hodgkin's lymphoma, and malignant germ cell tumors) groups. The sensitivity and specificity of maximum standardized uptake value (SUVmax) 7.5 for the detection of High group were 77% and 100%, respectively. The SUVmax distributions of the WHO histological thymoma types and Masaoka stage thymomas extensively overlapped. Masaoka stage III thymomas had significantly higher SUVmax than Masaoka stage I thymomas. Regarding the TNM classification, the SUVmax of T3 and T1b thymomas was higher than T1a thymoma. Although the SUVmax of each disease overlapped, PET/CT findings provided useful information for the differential diagnosis of anterior mediastinal masses.

Treatment of young adults with Philadelphia-negative acute lymphoblastic leukemia and lymphoblastic lymphoma: Hyper-CVAD vs. pediatric-inspired regimens.

For young adults with acute lymphoblastic leukemia, pediatric-based regimens are likely to provide the following when compared to hyper-CVAD regimens: better disease control, less hospitalization time, diminished acute toxicities, decreased financial cost, more quality-adjusted life years, and fewer adverse late effects, such as infertility, myelodysplasia, and second malignant neoplasms. There are also reasons to expect less cardiac and cognitive dysfunction after pediatric regimens. The improved quality and quantity of life associated with pediatric regimens renders them preferable to hyper-CVAD regimens for the treatment of Philadelphia-negative B-precursor or T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma in young adults.

A Young Man with a Mass: Non-Early Precursor T-Cell Lymphoblastic Lymphoma

A Young Man with a Mass: Non-Early Precursor T-Cell Lymphoblastic Lymphoma

Abstract 599: Secondary malignancies in temozolomide-treated metastatic pancreatic neuroendocrine tumors

Abstract Purpose: To determine the incidence of secondary malignancies in patients treated with temozolomide (TMZ) for metastatic pancreatic neuroendocrine tumors (PNET). Background: TMZ is an oral alkylating agent used to treat glioblastoma multiforme (GBM), refractory anaplastic astrocytoma (AA), and metastatic PNET. This imidazotetrazine analog of dacarbazine lacks the ability to directly crosslink DNA and is thought to be less leukemogenic than other alkylators. Given either alone, or in combination with other therapies, TMZ is associated with improved clinical outcomes. However, serious hematologic adverse events (HAEs) like agranulocytosis, lymphopenia and aplastic anemia are not uncommon. Until recently, metastatic PNET was primarily managed with somatostatin-analogs, but with more reports demonstrating therapeutic activity of TMZ-based regimens, it is anticipated that more patients with metastatic PNET will be exposed to TMZ. Methods: To determine the incidence of secondary malignancy in TMZ-treated PNET, a systematic review of all known clinical trials, case reports, and other relevant literature regarding PNET and TMZ published before September 2017 was conducted using PubMed, Embase, Cochrane Library, and the FDA database. Results: Twenty-one publications, including clinical trials, meta-analyses, case reports, and cohort studies were analyzed. HAEs ranged from agranulocytosis to myelodysplastic syndrome. No publications reported any secondary malignancies. Incidentally, at the University of Kansas Medical Center, 3 patients with TMZ-treated PNET developed hematologic malignancies. A 29-year-old female with metastatic PNET was treated with TMZ and subsequently developed acute myeloid leukemia (AML) with cytogenetics consistent with therapy-related leukemia. The second patient with TMZ-treated metastatic PNET developed diffuse large B-cell lymphoma. These two patients both had aggressive disease that was not responsive to multiple rounds of treatment. They succumbed to their hematologic malignancy, and not from metastatic PNET. The third patient is a 29-year-old who was recently diagnosed with high-grade T-cell lymphoblastic lymphoma and is currently undergoing treatment for his lymphoma. Conclusion: This review did not find any cases of secondary malignancy in TMZ-treated metastatic PNET. Yet, at our own institution we have identified 3 cases of secondary hematologic malignancies in patients treated with TMZ for PNET. We believe that the leukemogenic potential of TMZ is underreported and anticipate increased reports of secondary malignancy as the use of TMZ increases. It is important for treatment guidelines to address this risk in the decision to pursue TMZ treatment. Appropriate dosing, proper follow-up and surveillance, especially in patients who are able to live long enough to develop these hematologic cancers, is crucial. Citation Format: Nicole Balmaceda, Sunil Abhyankar, Tyler Mouw, Joaquina Baranda. Secondary malignancies in temozolomide-treated metastatic pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 599.

Abstract 1880: Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the canine model of non-Hodgkin lymphoma

Abstract Introduction: Lymphoma is a common, aggressive malignancy in dogs. While generally responsive to upfront combination chemotherapy with traditional cytotoxic drugs, remission times are short and cures rare. New treatment strategies are therefore needed. Protein arginine methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase (PRMT) enzyme whose relevance to cancer biology has become increasingly evident as more studies have shown this enzyme to be involved in the regulation of multiple major signaling pathways affecting cell death, proliferation, and malignant transformation. While the mechanism behind many of these cell-transforming capabilities of PRMT5 remains unknown, knockdown of PRMT5 expression by genetic or pharmacologic means has been shown to modulate the methylation status of target proteins and exert antitumor effects in vitro and in vivo. Consequently, PRMT5 small-molecule inhibitors are in early preclinical development. Methods: In this study, we characterized patterns of PRMT5 expression and correlated these with histologic subtype using canine lymphoma tissue microarrays (TMAs). We characterized expression of PRMT5 in canine lymphoma tissues and methylation targets in canine B-cell lymphoma cell lines and treated them with different PRMT5 inhibitors to determine effects on PRMT5, target proteins and antitumor activity. We also assessed PRMT5 inhibition ex vivo in patient B-cell lymphomas via flow cytometry and assessment of apoptosis with annexin V/PI staining. Results: Canine diffuse large B-cell lymphoma showed cytoplasmic staining for PRMT5 (48.8% strong, 50.0% weak, n = 165) compared to negative or weak staining in normal and hyperplastic lymph nodes (n = 40). Lymphoblastic T-cell lymphoma samples showed strong nuclear staining (40%, n= 10). No nuclear staining was appreciated in normal or hyperplastic lymph nodes. Similarly, canine B-cell lines showed high expression of PRMT5. PRMT5 small-molecule inhibitors inhibited growth of CLBL-1 and 17-71 canine lymphoma cell lines. Histone (H3R8 and H4R3) methylation status was suppressed at their respective IC50s. Ex vivo treatment of canine patient tumor cells showed suppression of growth at 24 hours. Conclusion: We have demonstrated that PRMT5 is expressed in canine lymphomas and that PRMT5 inhibition can suppress the growth of canine lymphoma cells, supporting the continued use of the spontaneous canine lymphoma model for the preclinical development of PRMT5 inhibitors. Citation Format: Kyle A. Renaldo, Lindsay E. Courtney, Konstantin Shilo, Robert A. Baiocchi, William C. Kisseberth. Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the canine model of non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1880.

Study of the role of microRNAs in T-cell lymphoblastic lymphoma development through the regulation of expression of FBXW7 gene.

Study of the role of microRNAs in T-cell lymphoblastic lymphoma development through the regulation of expression of FBXW7 gene.

FADD phosphorylation is altered in human T-cell lymphoblastic lymphoma.

FADD phosphorylation is altered in human T-cell lymphoblastic lymphoma.

MicroRNA-17 and the prognosis of human carcinomas: a systematic review and meta-analysis

ObjectiveAlthough the role of microRNA-17 (miR-17) has been identified as a tumour biomarker in various studies, its prognostic value in cancers remains unclear. Therefore, we performed a systematic review and...

RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas

BackgroundPrecursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the impact of the deregulation of other genes such as CDKN1C, E2F1, and TP53 remains to be clarified. Interestingly, experiments in mouse models have proven that conditional T-cell specific deletion of Cdkn1c gene may induce a differentiation block at the DN3 to DN4 transition, and that the loss of this gene in the absence of Tp53 led to aggressive thymic lymphomas.ResultsIn this manuscript, we demonstrated that the simultaneous deregulation of CDKN1C, E2F1, and TP53 genes by epigenetic mechanisms and/or the deregulation of specific microRNAs, together with additional impairing of TP53 function by the expression of dominant-negative isoforms are common features in primary human T-LBLs.ConclusionsPrevious experimental work in mice revealed that T-cell specific deletion of Cdkn1c accelerates lymphomagenesis in the absence of Tp53. If, as expected, the consequences of the deregulation of the CDKN1C-E2F1-TP53 axis were the same as those experimentally demonstrated in mouse models, the disruption of this axis might be useful to predict tumor aggressiveness, and to provide the basis towards the development of potential therapeutic strategiesin human T-LBL.

Deletion of RUNX1 exons 1 and 2 associated with familial platelet disorder with propensity to acute myeloid leukemia

Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) associated with RUNX1 mutations is an autosomal dominant disorder included in the group of the myeloid neoplasms with germ line predisposition. We describe two brothers who were diagnosed with hematological malignancies (one with AML and the other with T-cell lymphoblastic lymphoma). There was a history of leukemia in the paternal family and two of their siblings presented with low platelet counts and no history of significant bleeding. A microdeletion encompassing exons 1-2 of RUNX1 (outside the cluster region of the Runt Homology domain and the transactivation domain) was detected in six family members using array-CGH and MLPA validation. A low platelet count was not present in all deletion carriers and, therefore, it should not be used as an indication for screening in suspected families and family members.

Antitumor effect of triptolide in T-cell lymphoblastic lymphoma by inhibiting cell viability, invasion, and epithelial-mesenchymal transition via regulating the PI3K/AKT/mTOR pathway.

IntroductionT-cell lymphoblastic lymphoma (T-LBL) is a widely disseminated disease worldwide. Triptolide (TPL) is purified from Chinese herb and displays anti-inflammatory, anti-fertility, anti-tumor and immunosuppressive effects.Materials and methodsHere, in vitro and in vivo experiments were conducted to investigate the anti-tumor effect of TPL treatment in T-LBL and the potential mechanism in T-LBL progression.ResultsTPL inhibited cell proliferation of T-LBL cells (Jurkat cells and Molt-3 cells) in a dose-dependent manner. Flow cytometry analysis showed that cell apoptosis rate was increased by TPL treatment. TPL also up-regulated the expression of Caspase-3, Bax and down-regulated the expression of Bcl-2, indicating that TPL promoted apoptosis in Jurkat cells. Moreover, TPL inhibited invasion ability of Jurkat cells and down-regulated the expression of MMP-3 and MMP-9 in a dose-dependent manner. The expression of Snail, Slug, Twist and Integrin αVβ6 was decreased and the expression of E-cadherin was increased by TPL treatment, indicating that TPL inhibited EMT of Jurkat cells. Apart from that, TPL treatment attenuated the phoslevels of PI3K, Akt and mTOR and suppressed AKT activation compared with control group, suggesting that TPL inhibited PI3K/Akt/mTOR signal pathway in T-LBL. In vivo experiments showed that TPL inhibited tumor growth of T-LBL and promoted apoptosis of tumor cells. The expression of PCNA, Bcl-2, Snail, p-PI3K, p-Akt and mTOR was suppressed by TPL in a dose-dependent manner, suggesting that TPL suppressed tumor growth and promoted apoptosis of tumor cells by inhibiting PI3K/Akt/mTOR signal pathway in T-LBL.ConclusionIn conclusion, TPL exerted anti-tumor effect in T-LBL by inhibiting cell viability, invasion and EMT via regulating the PI3K/AKT/mTOR pathway.

Patients over 40 years old with precursor T-cell lymphoblastic lymphoma have different prognostic factors comparing to the youngers

This study aimed to analyze the clinical characteristics and prognostic factors of patients, divided into over 40-year-old group or not, with precursor T-cell lymphoblastic lymphoma (Pre-T-LBL). Based on the retrospective analysis of the clinical data of 59 patients with Pre-T-LBL during the period from December 2010 to December 2015, albumin level, anemia, pleural or pericardial effusion, protocol, therapy response, mediastinal mass, lactate dehydrogenase (LDH), and international prognostic index (IPI) or age-adjusted international prognostic index (aaIPI) were summarized. For patients aged <40 years, factors correlating with poor progression-free survival (PFS) were pleural or pericardial effusion, regimen, albumin level and therapy response. Pleural or pericardial effusion, aaIPI score, regimen, LDH increased, albumin level, therapy response and mediastinal mass were all related with poor overall survival (OS). In the patients aged ≥40 years, only anemia associated with PFS. However, anemia, involvement of bone marrow and therapeutic response were all related with poor OS. In conclusion, the patients with Pre-T-LBL are characterized by a low incidence and bad prognosis. Different prognostic factors can be discovered for patients over 40-year-old with Pre-T-LBL comparing to the youngers. New prognostic evaluation factors should be explored for patients ≥40 years old.