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So far, only very few AML patients, harboring a I CALR i mutation, have been described. Dear Editor, Core binding factor acute myeloid leukemia (AML) patients with the recurrent genetic anomaly I RUNX1-RUNX1T1 i represent an AML subgroup with favorable risk [[1]]. [[4], [6]] We report for the first time to our knowledge a case of an AML patient with I RUNX1-RUNX1T1 i translocation and concomitant I CALR i mutation. [Extracted from the article]

The detection of chromosomal translocations by fluorescence in situ hybridization (FISH) is widely performed, but very few studies have attempted to apply this technique to paraffin-embedded routine biopsy samples. We report the analysis of paraffin sections from 36 B-cell lymphoma biopsies for MYC translocation breakpoints by FISH. The probes consisted of multi-YAC constructs that flanked the breakpoint region and that, therefore, separate upon a chromosomal translocation and generate split (or 'segregated') signals (rather than a more ambiguous 'co-localization' pattern, obtained when the two partners in a hybrid gene are detected). The results were assessed by a simple approach that avoids the counting of signal numbers per nucleus and so is appropriate for use in routine practice. A total of 19 of the 36 lymphomas were scored as positive for MYC translocation and this included 16 of the 20 patients in whom classic cytogenetics had shown the presence of the (8;14) translocation (or one of its two variants). We conclude that this two-colour 'split-signal' technique based on breakpoint flanking probes can readily detect chromosomal translocations in paraffin sections. Furthermore, our results suggest that cases categorized as 'atypical Burkitt's/Burkitt-like' lymphoma (at least for adult patients) are heterogeneous with respect to translocations involving the MYC oncogene, as well as immunophenotype and clinical features. [ABSTRACT FROM AUTHOR]

There is controversy in the literature as to whether anaplastic large-cell lymphoma of B-cell phenotype is related to the t(2;5)-positive T- or ‘null’ cell lymphoma of the same morphology. We report a study of 24 lymphomas with morphological features of anaplastic large-cell lymphoma which expressed one or more B-cell markers and lacked T-lineage markers. Clinical features were more in keeping with large B-cell lymphoma than with classical t(2;5)-positive anaplastic large-cell lymphoma, and immunostaining for anaplastic lymphoma kinase (ALK) protein provided no evidence for the (2;5) translocation (or one of its variants). The staining patterns for CD20 and CD79 were typical of diffuse large B-cell lymphoma, CD30 expression was variable, and most cases (15/22) lacked epithelial membrane antigen (EMA). These findings support the view that ‘B-cell anaplastic large-cell lymphoma’ is unrelated to t(2;5)-positive (ALK‐positive) lymphoma, and that it represents a morphological pattern occasionally encountered among diffuse large B-cell lymphomas. By the same reasoning, most tumours diagnosed as ‘ALK‐negative anaplastic large‐cell lymphoma of T‐cell or null phenotype’ probably belong to the spectrum of peripheral T‐cell lymphomas. [ABSTRACT FROM AUTHOR]

There is increasing evidence that therapy-related acute lymphoblastic leukemia (trALL) resulting from chemo- and/or radiotherapy represents a distinct entity. However, apart from KMT2A rearrangements, which have been repeatedly reported in this subgroup, the relevance of other aberrations remains controversial due to divergent study results and sparse molecular analyses. Within our ALL patient cohort, 15% (n = 19/131) met the criteria for trALL with a high proportion of Ph + and KMT2A rearrangements. On the molecular level, the most frequently observed mutation was KMT2D, followed by CDKN2A, KRAS and DNMT3A. No TP53 mutation was detected. Outcome was particularly poor in Ph + trALL compared to Ph+ de novo ALL, which seemed to be mitigated by allogeneic stem cell transplantation. Our findings further define trALL as a distinct entity but highlight the need for further molecular genome sequencing of somatic and germline variants to advance our understanding of trALL. [ABSTRACT FROM AUTHOR]

Context.--Despite their stromal origin, follicular dendritic cells (FDCs) share many functions with hematopoietic system cells. FDC neoplasms are currently classified by the World Health Organization along with those of a histiocytic nature. However, the molecular alterations driving oncogenesis in FDC sarcomas (FDCSs) are beginning to be unveiled and do not seem to concur with those described in histiocytic neoplasms, namely MAPK pathway activation. Objective.--To identify molecular alterations driving tumorigenesis in FDCS. Design.--We investigated the role of MYC and TP53 in FDC-derived tumor oncogenesis and assessed comprehensively the status of the MAPK pathway in 16 FDCSs, 6 inflammatory pseudotumor (IPT)--like FDCSs, and 8 IPTs. Results.--MYC structural alterations (both amplifications and rearrangements) were identified in 5 of 14 FDCSs (35.7%), all associated with MYC overexpression. TP53 mutations were identified in 4 of 14 FDCSs (28.6%), all of which displayed intense and diffuse p53 expression. None of these alterations were identified in any IPT-like FDCSs or in IPT cases. No MAPK pathway gene alterations were identified in any of the cases studied. Conclusions.--The presence of MYC and TP53 alterations and the lack of association with Epstein-Barr virus segregate classical FDCS from IPT-like FDCS, pointing at different oncogenic mechanisms in both entities. Our results suggest a possible oncogenic role of MYC and TP53 alterations in FDCS. The absence of MAPK pathway alterations confirms the lack of a significant role of this pathway in the oncogenesis of FDC-derived neoplasms. [ABSTRACT FROM AUTHOR]

The article examines extranodal involvement of the head and neck region in adult T-cell leukemia/lymphoma (ATLL). ATLL represents a spectrum of malignant lymphoproliferative disorders that is invariably associated with infection by the human T-cell leukemia virus type 1. A study of Miyagi and colleagues provides evidence that ATLL should be a new and important member on the list of differential diagnosis.

Hoeller S, Schneider A, Haralambieva E, Dirnhofer S & Tzankov A (2010) Histopathology 57, 73–80 FOXP1 protein overexpression is associated with inferior outcome in nodal diffuse large B-cell lymphomas with non-germinal centre phenotype, independent of gains and structural aberrations at 3p14.1 Aims: To determine the molecular epidemiology and prognostic importance of structural and numeric FOXP1 gene aberrations with respect to BCL-6 gene and to FOXP1 protein expression in 389 diffuse large B-cell lymphomas (DLBCL) from the pre-rituximab era on tissue microarrays. Methods and results: By interphase fluorescence in situ hybridization with colour-labelled bacterial artificial chromosome clones, 12% (27/223) analysable cases showed FOXP1 gains and 1% (2/210) FOXP1 breaks. Seven percent of cases with known BCL-6 and FOXP1 gene status ( n = 159) showed an isolated FOXP1 gain, 19% an isolated BCL-6 gain and 18% a trisomy 3. FOXP1 gains (isolated and due to trisomy 3) were more frequent in nodal than extranodal DLBCL and in non-germinal centre B-cell-like (non-GCB) DLBCL than in GCB DLBCL. By immunohistochemistry, FOXP1 protein was more often overexpressed in non-GCB than in GCB cases. FOXP1 overexpression was associated with poor disease-specific survival in all DLBCL, particularly in nodal and non-GCB cases. There was no correlation between FOXP1 gene aberrations and either FOXP1 protein expression or survival. Conclusions: FOXP1 is recurrently targeted by numeric, and rarely by structural, genetic aberrations in DLBCL. Only the presence of FOXP1 protein, irrespective of its gene status, is decisive for prognosis in DLBCL. [ABSTRACT FROM AUTHOR]

Session 7 of the Society for Hematopathology/European Association for Haematopathology Workshop was devoted to case presentations and discussion of enteropathy-type T-cell lymphoma (ETL) and other T-cell lymphomas involving the gastrointestinal tract. ETL is a rare type of T-cell lymphoma, often associated with a history of celiac disease, that usually arises in the jejunum but can involve other gastrointestinal tract sites (eg, stomach and colon). As the cases submitted illustrate, there are 2 histologic groups of ETL that correlate with clinical and immunophenotypic features. Pleomorphic-anaplastic ETL is usually associated with a history of celiac disease and histologic evidence of enteropathy and is most often CD56-. Monomorphic ETL often occurs without a history of celiac disease, has variable histologic evidence of enteropathy, and is usually CD56+. Comparative genomic hybridization has shown recurrent chromosomal gains and losses that are characteristic of ETL and uncommon in other T-cell lymphomas, providing useful ancillary data for the diagnosis of ETL. [ABSTRACT FROM AUTHOR]

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response. [ABSTRACT FROM AUTHOR]

• Loss of protective antibody levels over time differed substantially between measles, mumps and rubella in patients following allogeneic hematopoietic cell transplantation (HCT). • Protective immunity against measles and rubella that was acquired by wild-type viral infection persisted longer than immunity due to vaccination. • Intensity of the conditioning regimen and the use of antithymocyte globulin had no influence on the decline of antibody titers against measles, mumps, and rubella post- HCT. • The presence of chronic graft-versus-host disease was associated with a more rapid loss of protective immunity against measles post-HCT. Outbreaks of viral infections, such as measles, are regularly observed and pose a serious threat to recipients of allogeneic hematopoietic cell transplantation (HCT). The questions of how long cellular and humoral protective host immunity persists, and whether donor immunity can be transferred has not been clarified. Here we present a retrospective analysis of humoral immunity—serial antibody titers against measles, mumps, and rubella—in 331 patients who underwent allogeneic HCT at our single center between 2002 and 2015. Associations between the loss of protective antibody levels and clinical patient characteristics and transplantation parameters were examined. In general, antibody protection against measles persisted longer, with 72% of patients maintaining sufficient titers at 5 years post-HCT even without revaccination, while at that time only 65% and 50% of patients had protective immunity against rubella and mumps, respectively. The great majority of donors were seropositive for all 3 viruses; however, it appeared that donor humoral immunity could not be transferred and had no impact on post-HCT serostatus. Rather, the most relevant factor for persistent protective antibody titers against measles and rubella was whether patients were born before the introduction of the respective vaccine and thus were immunized by the wild-type disease-inducing virus instead of the vaccine. Moreover, the presence of moderate and severe chronic graft-versus-host disease (GVHD) was associated with more rapid loss of immune protection. In contrast, underlying disease, intensity of the conditioning regimen, use of antithymocyte globulin, age, and graft source had no influence on antibody titers. Overall, our findings suggest that the majority of antibodies against measles, mumps, and rubella originate from residual host cells, whereas donor immune status appears to have no influence on antibody protection post-HCT. [ABSTRACT FROM AUTHOR]

Rare T- or NK-cell lymphomas with cutaneous manifestation may display a highly aggressive clinical course and major diagnostic/therapeutic challenges. This report describes our experiences with different lymphomas of this rare category and the therapeutic options used. This retrospective, descriptive, monocentric, cross-sectional case study, identified 4 rare aggressive T-/NK-cell lymphomas with manifestation in the skin, which were diagnosed in a tertiary care centre over a period of 4 years. Two patients had an Epstein-Barr virus-associated extranodal NK/T-cell lymphoma and 2 patients had a primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. Concomitant extracutaneous involvement was observed in 2 of all 4 patients. Two patients had fulminant disease progression and resistance to chemotherapy. Two patients underwent allogeneic haematopoietic stem cell transplantation, which resulted in one complete remission and one partial remission. This report emphasizes the importance of an early diagnostic work-up and a prompt aggressive therapeutic approach. [ABSTRACT FROM AUTHOR]

Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context. [ABSTRACT FROM AUTHOR]

Hepatitis C is frequently accompanied by immune-related extrahepatic manifestations affecting the skin, kidneys, central and peripheral nervous system and exocrine glands. We present the case of a 40-year-old man with left-sided ptosis, exophthalmos and headache. MRI demonstrated left-sided orbital pseudotumor with lacrimal and retro-orbital contrast enhancement extending to the cavernous sinus and the vestibulocochlear nerve. Immunological tests of serum and cerebrospinal fluid identified hepatitis C virus (HCV) as a potential causative agent but did not indicate any additional infectious, malignant or immunological disorder. Hepatological evaluation revealed no signs of advanced liver disease. After initial spontaneous improvement, the patient subsequently developed vestibulocochlear failure with gait disorder, tinnitus and transient left-parietal sensory loss. Lacrimal biopsy demonstrated lymphocytic infiltrate, prompting steroid treatment. After initial improvement, steroids could not be tapered below 40 mg daily for several months due to recurrent symptoms. Twelve months after the initial presentation, the patient's chronic HCV infection was successfully treated with sofosbuvir, simeprevir and ribavirin and he remains now free of symptoms without steroids. In patients with chronic hepatitis C, lymphocytic infiltrate of the salivary and lacrimal glands is a frequent phenomenon. However, the extent of the lymphocytic infiltrate beyond the lacrimal gland to the tip of the orbit, cavernous sinus and vestibulocochlear nerve as in our patient is highly unusual. For all symptomatic extrahepatic manifestations of hepatitis C infection, treatment of HCV as the underlying immune stimulus is recommended, and it helped to control the symptoms in our patient. In addition, long-term follow-up for recurrent lymphocyte infiltrate and development of lymphoma is warranted. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is a presentation of primary cutaneous T-cell lymphoma with adverse prognosis for patients with advanced stages of the disease. Refractory disease and advanced-stage disease require systemic therapy. We reported a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59-year-old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization–European Organisation for Research and Treatment of Cancer classification. First-line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa-2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high-dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Readministration of interferon alfa-2a as a maintenance treatment after the salvage autologous SCT resulted in a complete remission during a follow-up period of 32.5 months after autologous SCT. After that, the disease relapsed with simultaneous skin and cerebral lesions. Despite immediate intrathecal and subsequently intravenous administration of high-dose methotrexate and cytarabin, we observed further progressed and the patient deceased 3.5 months after this second fulminant recurrence and in total 36 months after autologous SCT transplantation. [ABSTRACT FROM AUTHOR]

The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain (IGH) locus or non-IG sequences. The former translocation, t(3;14)(p13;q32), results in dysregulated expression of FOXP1 juxtaposed with strong regulatory elements of IGH. Thus far, molecular consequences of rare non-IG aberrations of FOXP1 remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non-IG rearrangements of FOXP1 are usually acquired during clinical course of various lymphoma subtypes, including diffuse large B cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukemia, and correlate with a poor prognosis. Importantly, these aberrations constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non-IG rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms (FOXP1NT), as shown by QRT-PCR and Western blot analysis. In contrast, t(3;14)(p13;q32)/IGH-FOXP1 affects the 5′ untranslated region of FOXP1 and results in overexpress the full-length FOXP1 protein (FOXP1FL). RNA-sequencing of a few lymphoma cases expressing FOXP1NT and FOXP1FL detected neither FOXP1-related fusions nor FOXP1 mutations. Further bioinformatic analysis of RNA-sequencing data retrieved a set of genes, which may comprise direct or non-direct targets of FOXP1NT, potentially implicated in disease progression. In summary, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. We hypothesize that the primary t(3;14)(p13;q32)/IGH-FOXP1 activates expression of the FOXP1FL protein with potent oncogenic activity, whereas the secondary non-IG rearrangements of FOXP1 promote expression of the FOXP1NT proteins, likely driving progression of disease. [ABSTRACT FROM AUTHOR]

The B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCLs with an active host inflammatory response and has been suggested to be associated with interferon-related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFN?) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1. Remarkably, BAL1 stimulates the phosphorylation of both STAT1 isoforms, STAT1a and STAT1b, on Y701 and thereby promotes the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1b. Moreover, BAL1 physically interacts with both STAT1a and STAT1b through its macrodomains in an ADP-ribosylation-dependent manner. BAL1 directly inhibits, together with STAT1b, the expression of tumor suppressor and interferon response factor (IRF)-1. Conversely, BAL1 enhances the expression of the proto-oncogenes IRF2 and B-cell CLL/lymphoma (BCL)-6 in DLBCL. Our results show for the first time that BAL1 represses the anti-proliferative and pro-apoptotic IFN?-STAT1-IRF1-p53 axis and mediates proliferation, survival and chemoresistance in DLBCL. As a consequence constitutive IFN?-STAT1 signaling does not lead to apoptosis but rather to chemo-resistance in DLBCL overexpressing BAL1. Our results suggest that BAL1 may induce an switch in STAT1 from a tumor suppressor to an oncogene in high-risk DLBCL. [ABSTRACT FROM AUTHOR]

Abstract: Characterising tumour-associated antigens (TAAs) not only represents an important approach to the identification of new diagnostic/prognostic markers, but can also provide information on disease processes and additional potential therapeutic targets. Preliminary screening of a protein macroarray, containing more than 12,000 different proteins, with sera from anaplastic lymphoma kinase (ALK)-negative and ALK-positive anaplastic large cell lymphoma (ALCL) patients identified ribonuclease and tumour suppressor protein Ribonuclease T2 (RNASET2), phosphatase lipid phosphate phosphatase-related protein type 3 (LPPR3) and apoptotic adaptor molecule Fas-associating protein (FADD) as ALK-negative ALCL-associated TAAs. Further validation of these observations was confirmed using the ALCL sera in reverse ELISAs. The circulating anti-RNASET2 autoantibodies present in ALCL patients'' sera also recognised eukaryotically expressed RNASET2 protein. RNASET2 expression was then investigated in normal tissues and in lymphomas to explore its clinical potential. RNASET2 protein and mRNA levels showed highest expression in the spleen, leucocytes and pancreas. RNASET2 protein expression was not restricted to ALK-negative ALCL (81%), being expressed in ALK-positive ALCL (65%) as well as in a number of other lymphomas. The immunological recognition of RNASET2, its expression in ALCL and other lymphomas together with its known tumourigenic properties suggest that further studies on this autoantigen are warranted. [Copyright &y& Elsevier]

Extramedullary (e) relapse in multiple myeloma (MM) has an adverse prognosis, but knowledge concerning biological features and preferred treatment is scarce. We screened the myeloma registry of our institution for eMM relapses and identified 24 cases among 357 patients (pts). Only 8% of eMM relapses occurred after initial therapy, but 54% occurred after third-line or subsequent therapy. Baseline molecular cytogenetics revealed high-risk features in 10 of 19 evaluable patients. Most frequently, eMM presented as soft tissue (67%) and organ involvement (25%) or malignant effusion (12.5%). Incidence of leptomeningeal/CNS involvement was 21%. At eMM relapse, bone marrow infiltration was absent in 46% and low in 21%. Ten eMM biopsies were available showing increased proliferation, i.e., Ki-67 of 67% (range, 30-90%) of all cancer cells. Pts received radiation therapy, dose-intense chemotherapy, novel agents, and allogeneic SCT resulting in an overall response rate of 54%. Median progression-free survival was 2 (95% CI 0.08-3.92) and median overall survival 7 months (95% CI 3.56-10.43), respectively, with only three patients being alive at 12 months from diagnosis. EMM relapse may present at any anatomical site with frequent CNS involvement. Biological features include increased proliferation and low rate of marrow involvement. Prognosis remains poor despite intensive treatment. [ABSTRACT FROM AUTHOR]

A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)-negative FLs remain largely unknown. We performed microRNA expression analysis in 32 FL grades 1 to 3A, including 17 t(14;18)-positive FLs, 9 t(14;18)-negative FLs without BCL2 expression, and 6 t(14;18)-negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)-positive FLs and t(14;18)-negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)-negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a "late" germinal center B-cell phenotype. [ABSTRACT FROM AUTHOR]

• SAMHD1 is recurrently mutated in mantle cell lymphoma. • SAMHD1 mutated MCL cells are less sensitive to nucleoside analogues in vitro. • SAMHD1 mutations are a potential drug target in MCL. [ABSTRACT FROM AUTHOR]

Background: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas. Methods: We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization. Results: We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course. Conclusions: Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome. N Engl J Med 2006;354:2419-30. [ABSTRACT FROM AUTHOR]