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The article presents a study that determines the role of CDK9 inhibitor in inducing durable apoptotic response in aggressive B-cell lymphoma. Overview of the background of the study which describe the durable responses to dinaciclib in aggressive MYC-driven lymphoma is provided. The result of the study which suggests that CDK9 inhibitors are highly effective MYC-driven lymphomas.

Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC. [ABSTRACT FROM AUTHOR]

The article discusses the combination of lymphodepletion with the infusion of donor T cells to carry a suicide gene for treatment of aggressive hematologic malignancies. A significant increase in the proportion of HLA-DR-expressing T cells is noted. An acute-like graft-versus-host disease is found in three patients after cell infusion. The use of lymphodepletion before cell infusion is considered helpful to improve the antitumor effect.

Acute myeloid leukemia (AML) is a biologically heterogeneous group of related diseases in urgent need of better therapeutic options. Despite this heterogeneity, overexpression of the interleukin (IL)-3 receptor α-chain (IL-3 Rα/CD123) on both the blast and leukemic stem cell (LSC) populations is a common occurrence, a finding that has generated wide interest in devising new therapeutic approaches that target CD123 in AML patients. We report here the development of CSL362, a monoclonal antibody to CD123 that has been humanized, affinity-matured and Fc-engineered for increased affinity for human CD16 (FcγRIIIa). In vitro studies demonstrated that CSL362 potently induces antibody-dependent cell-mediated cytotoxicity of both AML blasts and CD34+CD38−CD123+ LSC by NK cells. Importantly, CSL362 was highly effective in vivo reducing leukemic cell growth in AML xenograft mouse models and potently depleting plasmacytoid dendritic cells and basophils in cynomolgus monkeys. Significantly, we demonstrated CSL362-dependent autologous depletion of AML blasts ex vivo, indicating that CSL362 enables the efficient killing of AML cells by the patient's own NK cells. These studies offer a new therapeutic option for AML patients with adequate NK-cell function and warrant the clinical development of CSL362 for the treatment of AML. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to microRNA activity signatures associated with peripheral T cell lymphoma subtypes in the May 10, 2013 issue.

The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m2/day, days 1-5, every 28 days) followed by DLI (from 1-5 × 106 to 1-5 × 108 CD3+cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 23%) and two partial remissions (7%). Five patients remain in CR for a median of 777 days (range 461-888). Patients with MDS or AML with myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, respectively. Neutropenia and thrombocytopenia grade III/IV occurred during 65% and 63% of treatment cycles, while infections were the most common grade III/IV non-hematological toxicity. Azacitidine and DLI as salvage therapy is safe, induces long-term remissions and may become an alternative for patients with AML or MDS relapsing after allo-HSCT. [ABSTRACT FROM AUTHOR]

A letter to the editor commenting on a study related to specific deletion of TRAF3 in B lymphocytes leading to B-lymphoma development in mice is presented.

Accumulating evidences indicate that the cellular and molecular microenvironment of follicular lymphoma (FL) has a key role in both lymphomagenesis and patient outcome. Malignant FL B cells are found admixed to specific stromal and immune cell subsets, in particular CD4pos T cells displaying phenotypic features of follicular helper T cells (TFH). The goal of our study was to functionally characterize intratumoral CD4pos T cells. We showed that CXCR5hiICOShiCD4pos T cells sorted from FL biopsies comprise at least two separate cell populations with distinct genetic and functional features: (i) CD25pos follicular regulatory T cells (TFR), and (ii) CD25neg TFH displaying a FL-B cell supportive activity without regulatory functions. Furthermore, despite their strong similarities with tonsil-derived TFH, purified FL-derived TFH displayed a specific gene expression profile including an overexpression of several genes potentially involved directly or indirectly in lymphomagenesis, in particular TNF, LTA, IL4 or CD40LG. Interestingly, we further demonstrated that these two last signals efficiently rescued malignant B cells from spontaneous and rituximab-induced apoptosis. Altogether, our study demonstrates that tumor-infiltrating CD4pos T cells are more heterogeneous than previously presumed, and underlines for the first time the crucial role of TFH in the complex set of cellular interactions within FL microenvironment. [ABSTRACT FROM AUTHOR]

B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell-cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3'UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas. [ABSTRACT FROM AUTHOR]

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of chronic inflammation caused by Helicobacter pylori infection. Most pathophysiological features of the early stages of MALT lymphomagenesis can be reproduced by experimental infection of BALB/c mice with Helicobacter species. We have previously shown that MALT lymphomas are infiltrated by T-helper cell type 2-polarized T cells and that human and murine tumor B cells carry polyreactive surface immunoglobulins. Using the murine model of the disease, in this study we show that explanted tumor B cells proliferate upon stimulation with the same panel of self and foreign antigens that are recognized by their surface antibodies. Tumor cell proliferation is strongly enhanced by the presence of intratumoral CD4+ T cells in a CD40/CD40L-independent manner. A large proportion of tumor-infiltrating CD4+ T cells are CD25+FoxP3+ regulatory T cells (Tregs) with highly suppressive activity, which are recruited by the tumor cells through secretion of the Treg-attracting chemokines CCL17 and CCL22. The depletion of CD25+ cells was as efficient as CD4+ T cell depletion in blocking tumor growth in vitro and in vivo. In conclusion, our data suggest that B-cell receptor-derived signals cooperate with T-helper cell signals in driving the progression of MALT lymphoma, providing an explanation for the unique antigen dependence of this B-cell malignancy. [ABSTRACT FROM AUTHOR]

STAT1 and STAT3 are the main mediators of the signaling of interferons (IFNs) and of gp130 cytokines, respectively. Neoplastic T lymphocytes frequently become resistant to the IFN-γ/STAT1 apoptotic pathway, often because of the downregulation of the IFN-γR2 receptor chain. Many studies suggest that cross-regulation between different STATs, in particular between STAT1 and STAT3, may profoundly affect cytokine/growth factor signaling. Here, the function of STAT3 in the negative regulation of STAT1 apoptotic pathway was investigated by RNA interference-mediated STAT3 silencing in human malignant T lymphocytes. In STAT3-depleted cells, interleukin (IL)-6 acquired the capacity to induce apoptosis, correlating with prolonged STAT1 activation and the induction of major histocompatibility complex (MHC) class I expression. In contrast, in the absence of STAT3, IFN-γ could slightly enhance apoptosis but its ability to induce MHC class I expression was unchanged. Accordingly, IL-6, but not IFN-γ, could significantly impair the in vivo growth of STAT3-depleted human neoplastic T lymphocytes transplanted into severe combined immunodeficient mice. Therefore, treatment with IL-6 and simultaneous STAT3 silencing may represent a potential therapeutic approach to control the expansion of IFN-γ-unresponsive neoplastic T cells. [ABSTRACT FROM AUTHOR]

Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF-kappaB) activity in reporter assays which is in keeping with a constitutive NF-kappaB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease. [ABSTRACT FROM AUTHOR]

The article discusses the role of allogeneic hematopoietic cell transplantation (HCT) in treating hematologic malignancies. It says that HCT represents a potentially curative treatment for several hematologic malignancies. Meanwhile, the curative principle in allogeneic HCT with NMA conditioning is solely related to the graft-versus-leukemia (GVL) effect, and several lines of evidence strongly suggest that donor T cells are the main effectors.

This article discusses research into the dysfunctional expression of microRNA in the development of lymphocytic disorders. MicroRNA regulates gene expression in cells. The use of microarray analysis to determine microRNA expression in hematological cell lines with diseases including lymphoma, nonmalignant lymphoproliferative disorder, and acute myeloid leukemia is noted.

A letter to the editor is presented about the absence of nucleophosmin leukaemic mutants in B and T cells from AML with NPM1 mutations that is published within the issue.

To test the role of telomere biology in T-cell prolymphocytic leukemia (T-PLL), a rare aggressive disease characterized by the expansion of a T-cell clone derived from immuno-competent post-thymic T-lymphocytes, we analyzed telomere length and telomerase activity in subsets of peripheral blood leukocytes from 11 newly diagnosed or relapsed patients with sporadic T-PLL. Telomere length values of the leukemic T cells (mean±s.d.: 1.53±0.65 kb) were all below the 1st percentile of telomere length values observed in T cells from healthy age-matched controls whereas telomere length of normal T- and B cells fell between the 1st and 99th percentile of the normal distribution. Leukemic T cells exhibited high levels of telomerase and were sensitive to the telomerase inhibitor BIBR1532 at doses that showed no effect on normal, unstimulated T cells. Targeting the short telomeres and telomerase activity in T-PLL seems an attractive strategy for the future treatment of this devastating disease.Leukemia (2007) 21, 2456–2462; doi:10.1038/sj.leu.2404968; published online 27 September 2007 [ABSTRACT FROM AUTHOR]

Using polymerase chain reaction (PCR)-based sequence-specific primers, the killer immunoglobulin-like receptor (KIR) genotypes of 35 patients with natural killer (NK)-type lymphoproliferative disease of granular lymphocytes and of 50 normal subjects were investigated to evaluate whether genes coding for activating KIRs were more frequently detected in patients with NK-lymphoproliferative disease of granular lymphocytes (LDGL). Genotype frequency indicated that the most frequently found gene content was eight genes in controls and 14 in patients (P<0.05). The KIR genotype analysis revealed that patient and, surprisingly, control KIR genotypes preferentially consisted of type B haplotypes characterized by the presence of multiple-activating KIRs. Evidence was also provided that the same KIR genotype was shared by a variable number of patients. Interestingly, the recurrent genotypes observed in the patient group were not found in controls. Concerning inhibitory genes, KIR2DL5a and 2DL5b were more frequently detected in patients than in controls (P<0.01), likely representing a discrete feature of the genetic repertoire of the patients. KIR gene repertoire analysis in patients suggests that the susceptibility to NK-LDGL might be related to the presence of activating KIR genes and supports the concept that these receptors may be involved in the priming of granular lymphocytes (GL) proliferation. Population analysis might disclose a genetic background predisposing to this disease.Leukemia (2007) 21, 1060–1069. doi:10.1038/sj.leu.2404634; published online 15 March 2007 [ABSTRACT FROM AUTHOR]

In this study, we show that high serum levels of soluble human leukocyte antigens (HLA) class I molecules (sHLA-I, range: 0.7–1.7 μg/ml) and soluble Fas ligand (FasL, range: 0.4–1.9 ng/ml) are detected in patients with acute myeloid leukemia (AML) at diagnosis, compared with healthy donors (HD) (sHLA-I, range: 0.1–0.6 μg/ml; sFasL, range: 0.1–0.4 ng/ml). Patients' sera were able to induce transcription and secretion of FasL in CD8+ T cells, followed by apoptosis in vitro; this apoptosis was inhibited by anti-HLA-I-specific monoclonal antibodies, suggesting that sHLA-I is responsible for cell death. These findings closely relate to the in vivo upregulation of FasL transcription observed in peripheral blood (PB) lymphocytes from AML patients; in the same cells, mRNA for the antiapoptotic proteins Bcl-2 and Bcl-xL was downregulated. Interestingly, caspase-8 and caspase-3, both downstream mediators of death receptor-induced apoptosis, were activated in CD8+ cells of AML patients; one-third of these cells were already apoptotic in vivo, at variance with lymphocytes of HD. These data strongly suggest that in AML, increased levels of sHLA-I molecules may contribute to the elimination of potentially anti-tumor effector cells through a FasL/Fas interaction.Leukemia (2007) 21, 253–260. doi:10.1038/sj.leu.2404494; published online 14 December 2006 [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) B-cells are hyporesponsive to many proliferative signals that induce activation of normal B-lymphocytes. However, a heterogeneous response has recently been observed with immunostimulatory CpG-oligodeoxynucleotides (CpG ODN). We now show that CpG ODN induce proliferation mainly in CLL B-cells from patients with progressive disease and unmutated immunoglobulin VH genes, whereas G1/S cell cycle arrest and apoptosis are induced in leukemic B-cells from stable/VH mutated CLL. Examination of early signaling events demonstrated that all CLL B-cells respond to CpG ODN stimulation by degradation of the NF-κB inhibitor IκB and activation of the Akt, ERK, JNK and p38 MAPK kinases, but the magnitude and duration of the signaling response was greater in the proliferating cases. Pharmacological inhibition of these pathways showed that simultaneous activation of Akt, ERK and JNK is required for cell cycle progression and proliferation. Conversely, introduction of constitutively active Akt in nonproliferating CLL B-cells resulted in induction of cyclin A following CpG ODN stimulation, indicating that increased Akt activation is sufficient to overcome the hyporesponsiveness of these cells to proliferative signals. Thus, the magnitude of Akt signaling may determine the distinct responses observed in leukemic B-cells belonging to the different prognostic subgroups.Leukemia (2007) 21, 110–120. doi:10.1038/sj.leu.2404417; published online 5 October 2006 [ABSTRACT FROM AUTHOR]

We have previously reported that alloreaction can lead to activation of dendritic cells through secretion of inflammatory cytokines. Here, we addressed whether alloreaction-derived cytokines may also lead to acute myelogenous leukemia (AML) blast differentiation. With this aim, supernatant (sn) harvested from major or minor histocompatibility antigen-mismatched mixed lymphocyte reaction (MLR) were used to culture French American Bristish (FAB) type M4 or M5 AML blasts. Our results showed that the secreted factors induced upregulation of CD40, CD54, and/or HLA molecules in AML blasts. Protein fractionation, blockade experiments and exogenous cytokine reconstitution demonstrated the involvement of TNF in the upregulation of CD54, CD40 and HLA-class II molecules, and of IFNγ in the increase of HLA-class I and class II molecule expression. But, in line of its much higher levels of secretion, TNFβ, rather than TNFα, was likely to play a preponderant role in AML blast differentiation. Moreover TNFβ and IFNγ were also likely to be involved in the AML blast differentiation-mediated by HLA-identical donor T-cell alloresponse against recipient AML blasts. In conclusion, we show herein that upon allogeneic reaction, TNFβ secretion contributes, in concert with IFNγ, to increase or restore surface molecules involved in AML blast interaction with T cells.Leukemia (2006) 20, 1992–2001. doi:10.1038/sj.leu.2404375; published online 14 September 2006 [ABSTRACT FROM AUTHOR]

Many acute lymphoblastic leukemias can be considered as malignant counterparts of cells in the various stages of normal lymphoid development in bone marrow and thymus. T-cell development in the thymus is an ordered and tightly controlled process. Two evolutionary conserved signaling pathways, which were first discovered in Drosophila, control the earliest steps of T-cell development. These are the Notch and Wnt-signaling routes, which both are deregulated in several types of leukemias. In this review we discuss both pathways, with respect to their signaling mechanisms, functions during T-cell development and their roles in development of leukemias, especially T-cell acute lymphoblastic leukemia.Leukemia (2006) 20, 1197–1205. doi:10.1038/sj.leu.2404255; published online 11 May 2006 [ABSTRACT FROM AUTHOR]

Strong expression of at least one of the three D-type cyclins is common in human cancers. While the cyclin D1 and D3 genes (CCND1 and CCND3) are recurrently involved in genomic rearrangements, especially in B-cell lymphoid neoplasias, no clear involvement of the cyclin D2 gene (CCND2) has been reported to date. Here, we identified chromosomal translocations targeting the CCND2 locus at 12p13, and the T-cell receptor beta (TCRB) or the TCRA/D loci in T-cell acute lymphoblastic leukemias (T-ALLs). Expression analysis demonstrated dramatic cyclin D2 overexpression in the translocated cases (n=3) compared to other T-ALLs (total, n=89). In order to evaluate dysregulation in T-ALL with respect to normal T-cell differentiation, we analyzed CCND2 expression in normal purified human thymic subpopulations. CCND2 levels were downregulated through progression from the early stages of human T-cell differentiation, further suggesting that the massive and sustained expression in the CCND2-rearranged T-ALL cases was oncogenic. Association with other oncogene expression (TAL1, HOXAs, or TLX3/HOX11L2), NOTCH1 activating mutations, and/or CDKN2A/p16/ARF deletion, showed that cyclin D2 dysregulation could contribute to multi-event oncogenesis in various T-ALL groups. This report is the first clear evidence of a direct involvement of cyclin D2 in human cancer due to recurrent somatic genetic alterations.Leukemia (2006) 20, 82–86. doi:10.1038/sj.leu.2404008; published online 3 November 2005 [ABSTRACT FROM AUTHOR]

Rearrangements of the MLL gene occur in both acute lymphoblastic and acute myeloid leukemias (ALL, AML). This study addressed the global gene expression pattern of these two leukemia subtypes with respect to common deregulated pathways and lineage-associated differences. We analyzed 73 t(11q23)/MLL leukemias in comparison to 290 other acute leukemias and demonstrate that 11q23 leukemias combined are characterized by a common specific gene expression signature. Additionally, in unsupervised and supervised data analysis algorithms, ALL and AML cases with t(11q23) segregate according to the lineage they are derived from, that is, myeloid or lymphoid, respectively. This segregation can be explained by a highly differing transcriptional program. Through the use of novel biological network analyses, essential regulators of early B cell development, PAX5 and EBF, were shown to be associated with a clear B-lineage commitment in lymphoblastic t(11q23)/MLL leukemias. Also, the influence of the different MLL translocation partners on the transcriptional program was directly assessed. Interestingly, gene expression profiling did not reveal a clear distinct pattern associated with one of the analyzed partner genes. Taken together, the identified molecular expression pattern of MLL fusion gene samples and biological networks revealed new insights into the aberrant transcriptional program in 11q23/MLL leukemias. [ABSTRACT FROM AUTHOR]

A total of 40 patients with B-CLL were investigated for CD5-triggered apoptosis and categorized as 20 resistant (group I) and 20 sensitive patients (group II). The densities of surface IgM (sIgM) and CD5 were lower in group I than group II, as were the percentages of CD79b+, CD38+, and Zap70-expressing B cells. CD5 signaling was mediated through the BCR in group II B cells, as established by coimmunoprecipitation of CD5 and CD79a and tyrosine phosphorylation of CD79a. Following colocalization of CD5 and sIgM in membrane lipid rafts (LRs), Syk became associated with these molecules, whereas SHP-1 was uncoupled from CD5. Nonresponsiveness to CD5 cross-linking in group I was ascribed to three possible abnormalities, and defined as three subgroups of patients. In subgroups Ia and Ib, CD5 and sIgM colocalized within the LRs. SHP-1 remained attached to the BCR in subgroup Ia, but not in subgroup Ib, where signal transduction was associated with an excess of truncated CD79b. In subgroup Ic, CD5 and sIgM segregated into different LRs, resulting in no signaling of apoptosis.Leukemia (2005) 19, 223-229. doi:10.1038/sj.leu.2403601 Published online 16 December 2004 [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease develops in severe combined immunodeficient (SCID) mice inoculated with peripheral blood mononuclear cells (PBMC) from EBV[SUP+] individuals (SCID/hu mice). In this study, we investigated the contribution of EBV reactivation and de novo infection of B lymphocytes to tumor outgrowth in SCID/hu mice. Evaluation of BZLF-1, an early EBV activation transcript, in cells recovered from the mouse peritoneal cavity within 16 days following PBMC transfer did not reveal EBV reactivation, while BZLF-1 expression was only detected in tumor masses or in vitro established lymphoblastoid cell lines. To confirm these data by a different strategy, we coinjected PBMC from seropositive donors with purified B cells from seronegative donors of different sex. Fluorescence in situ hydridization analysis of the resulting tumor masses disclosed that the overwhelming majority of lymphoma cells originated from the seropositive donor, implying that no substantial in vivo production and transmission of virus had occurred. Further, treatment of SCID/hu mice with ganciclovir did not prevent lymphoma development. Our results suggest that in the SCID/ hu mouse, early EBV replication and secondary infection of bystander B cells does not occur, and that the direct outgrowth of the transformed B lymphocytes present within the PBMC inoculum is the predominant mechanism, which leads to lymphoma generation in this experimental model. [ABSTRACT FROM AUTHOR]

The canine DLC 01 cell line derives from a lymph node of a dog with Sézary syndrome. The DLC 01 cell phenotype is CD4-, CD8+, CD45+, DQ+, similar to that of original cells after treatment with dimethylsulfoxide or phorbol myristate. Canine cutaneous T cell lymphoma are usually CD4-, CD8+ in contrast to their human counterparts which are CD4+, CD8-. Therefore, the DLC 01 cell line appears to be a unique model to study the mechanism of all surface molecule expression in vitro. Viral particles with retrovirus type-C morphology were found in ultrathin sections of DLC 01 cell pellets. Retroviral particles are spontaneously produced after the 50th cell passage or after induction with 0.5% dimethylsulfoxide. This is the first description of a dog lymphoid cell line spontaneously growing and producing a retrovirus. It was found to share several features in common with feline and murine leukemia viruses. [ABSTRACT FROM AUTHOR]

We studied the compatibility of human lymphocyte engraftment and susceptibility to HIV-1 infection in 2 new immunodeficient mice. NOD/Shi-scid mice were generated by backcrossing of the scid mutation into NOD mice while C57BL/6-RAG20/0 were generated by knocking out the RAG-2 gene. Human T lymphocytes were reconstituted in new immunodeficient mouse strains. We found that the new immunodeficient mouse strains accepted human PBL engraftment and HIV-1 infection more efficiently than conventional C.B-17-scid mice. Especially in the hu-PBL-NOD/Shi-scid strain, we reproduced the high levels of HIV-1 viremia comparable to or at significantly higher levels than after HIV-1 primary infection. These results indicate that our hu-PBL-NOD-scid animal is useful for investigations of the activation mechanism in HIV-1 replication in vivo and after primary infection. [ABSTRACT FROM AUTHOR]

The article presents a study on the effectiveness of cyclophosphamide as a first-line therapy in large granular lymphocyte (LGL) leukemia which could be an interesting alternative to methotrexate. It reveals that cyclophosphamide should be given to patients for at least 4 months before changing drug regimen. It also notes that cyclophosphamide is effective in T/NK-LGL leukemia, in both neutropenic and anemic patients, based on a series of study conducted.

The article presents a study which determines high specific STAT3 mutations for large granular lymphocytic leukemia. The study analyzed and compared the frequency and potential prognostic impact of STAT3 mutations in 56 patients with large granular lymphocytic (T-LGL) leukemia and cases with other T-cell malignancies and reactive conditions. Results of the study confirmed the presence of STAT3 mutations in T-LGL higher frequency of 72.7%.

This article discusses a study which investigated whether primary graft-versus-leukemia (GvL) responses can be efficiently elicited against established human acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphoid blastic phase (CML-BP) in NOD/sci mice after treatment with human leukocyte antigen (HLA)-matched donor lymphocyte infusion (DLI). Researchers engrafted NOD/scid mice with leukemic cells from different patients and treated with DLI from HLA-matched donors.

Feline leukemia virus (FeLV) infection in cats serves as a valuable animal model system for understanding the mechanisms of human diseases such as cancer and immunodeficiency. We have used experimental infection with molecularly cloned viruses to isolate and characterize novel FeLV variants that evolved in vivo and that were associated with the development of thymic lymphoma. One variant, FeLV-81T, contained a mutated envelope gene that conferred cytopathicity, enhanced replication rate, and syncytium induction in feline T cells, and is reminiscent of immunodeficiency-inducing strains of FeLV. Another variant transduced a portion of the feline Notch2 gene, which was expressed as a novel truncated protein in the cell nucleus and which we believe functioned as an oncogene in the development of T cell malignancy. Understanding how FeLV variants that either stimulate or destroy lymphocytes evolve and interrelate during disease progression will help elucidate the mechanisms of retroviral pathogenicity. [ABSTRACT FROM AUTHOR]

Histological study revealed that Marek's disease virus (MDV) can cause apoptosis in peripheral blood lymphocytes (PBL) in latently infected chickens. Analysis of DNA fragmentation indicated that CD4+T cells but not CD8+T cells underwent apoptosis. These apoptotic changes were also observed in the thymus during the acute phase of the infection. Flow cytometry analysis showed the drastic decrease of CD4+CD8+ thymocytes, indicating that MDV can induce apoptosis in CD4+CD8+immature thymocytes in acutely infected chickens. These changes might be involved in the immuno-suppression induced by MDV. [ABSTRACT FROM AUTHOR]

Studies the survival of chronic lymphocytic leukemia (CLL) cells. Examination on the connection between CD40L and the vascular endothelial growth factor; Characterization of common adult leukemia by accumulation of lymphocytes that do not like to undergo apoptosis; Identification of the mechanisms that are most critical to the apoptosis resistance of CLL B cells.

Presents a case study on spontaneous remission of large granular lymphocyte (LGL) T cell Leukemia. Rearrangement of the T cell receptor gene; Features of lymphocytes found in peripheral blood and bone marrow of the patient under study; Treatment of the patient with antibiotics.

Replies to comments made on the article 'Large Cell Lymphoma Complicating Persistant Polyclonal B Cell Lymphocytosis,' published in the journal 'Leukemia.' Case study of patients diagnosed with persistant polyclonal lymphocytosis (PPBL); Additional subjects reported related to PPBL patients; Differences in cytogenetics methodology.