B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer ...telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes. (Blood. 2005;105:4807-4812)
BACKGROUNDThe infiltration of regulatory T cells (Tregs) in lymphomas is associated with better prognosis for some types of lymphomas, but knowledge of their role in posttransplant ...lymphoproliferative disorders (PTLDs) is limited. We therefore investigated the association between the expression of the Treg marker forkhead box protein 3 (FoxP3) in biopsies of PTLDs and survival, PTLD subtype, and clinical characteristics.
METHODSSeventy-four cases of PTLD after solid organ transplantation with sufficient material for further analysis were included from a population-based study of PTLDs in Sweden. The PTLD biopsies were reevaluated and stained with the 236A/E7 antibody to detect FoxP3 in lymphoma tissue. Detailed clinical data were collected retrospectively from medical records.
RESULTSBased on a cutoff level of 29 FoxP3 cells per mm, most (80%) of the PTLDs were FoxP3. Forty-seven of 74 PTLDs displayed no FoxP3 cells at all. The frequency of FoxP3 cells did not influence median overall survival. The FoxP3 PTLDs were more frequently of T-cell phenotype (P = 0.04), located at the graft (P = 0.03), occurred earlier after transplantation (P = 0.04), were more likely to develop in lung recipients (P = 0.04), and in patients that had received anti–T-cell globulin as induction therapy (P = 0.02). The FoxP3 PTLDs were associated with hepatitis C seropositivity (P = 0.03). In multivariate analysis, B-cell PTLD and hepatitis C infection were independent predictors of FoxP3 positivity.
CONCLUSIONOur findings suggest that intratumoral FoxP3 Tregs do not influence survival in patients with PTLD. FoxP3 Tregs are rare in PTLD, possibly because of heavy immunosuppression.
Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of ...AML, leading to improved risk stratification and new therapeutic options. However, multi–whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.
•Mutations in ARID1A and CSF1R are recurrently gained at relapse in AML and represent novel therapeutic options for patients with relapsed AML.•Recurrent somatic mutations in H3F3A and UBTF are age specific in relapsed AML, detected solely in adult and pediatric AML, respectively.
Display omitted
Background: The incidence of malignant lymphomas has been increasing rapidly, but the causes of these malignancies remain poorly understood. One hypothesis holds that exposure to ultraviolet (UV) ...radiation increases lymphoma risk. We tested this hypothesis in a population-based case–control study in Denmark and Sweden. Methods: A total of 3740 patients diagnosed between October 1, 1999, and August 30, 2002, with incident malignant lymphomas, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, and 3187 population controls provided detailed information on history of UV exposure and skin cancer and information on other possible risk factors for lymphomas. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression. Statistical tests were two-sided. Results: Multivariable-adjusted analyses revealed consistent, statistically significant negative associations between various measures of UV light exposure and risk of non-Hodgkin lymphoma. A high frequency of sun bathing and sunburns at age 20 years and 5–10 years before the interview and sun vacations abroad were associated with 30%–40% reduced risks of non-Hodgkin lymphoma (e.g., for sunbathing four times a week or more at age 20 versus never sunbathing, OR = 0.7, 95% CI = 0.6 to 0.9; for two or more sunburns a year at age 20 versus no sunburns, OR = 0.6, 95% CI = 0.5 to 0.8). These inverse associations increased in strength with increasing levels of exposure (all Ptrend≤.01). Similar, albeit weaker, associations were observed for Hodgkin lymphoma. There were no clear differences among non-Hodgkin lymphoma subtypes, although associations were stronger for B-cell than for T-cell lymphomas. A history of skin cancer was associated with a doubling in risks of both non-Hodgkin and Hodgkin lymphoma. Conclusions: A history of high UV exposure was associated with reduced risk of non-Hodgkin lymphoma. The positive association between skin cancer and malignant lymphomas is, therefore, unlikely to be mediated by UV exposure.
Background: Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of ...lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. Methods: In a population-based case–control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. Results: Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. Conclusions: Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.
Diffuse large B-cell lymphoma (DLBCL) has been shown to be comprised of at least two prognostic entities, depending on its resemblance to normal germinal center or activated B cells, using global ...gene expression profiling. Also, the expression patterns of bcl-6, CD10 and IRF-4 (also known as MUM1) have been suggested as alternative means of identifying the germinal- and nongerminal center (activated B-cell like) groups. In the present study, we evaluated by immunohistochemistry the expression patterns of CD10, bcl-6, IRF-4 and bcl-2 in a large material of 161 DLBCL patients. Using two different approaches, patients with germinal center phenotype displayed a significantly better survival than the nongerminal center group. Positive staining for bcl-6 or CD10 predicted for superior survival, while expression of IRF-4 alone showed no association with prognosis. Furthermore, expression of bcl-2 was associated with worse event-free survival and overall survival. In a multivariate analysis, a high international prognostic index score (3–5), non-GC phenotype and bcl-2 were independent adverse prognostic factors. Here we confirm the prognostic importance of determining the germinal- or nongerminal center phenotype in patients with DLBCL.
Objectives
Investigating expression of possible targets for proteasome inhibitors in patients with diffuse large B‐cell lymphoma (DLBCL) and correlating the findings to clinical parameters and ...outcome.
Methods
Tumour material from 92 patients with DLBCL treated with either R‐CHOP like (n = 69) or CHOP like (n = 23) regimens were stained for possible targets of proteasome inhibitors.
Results
The primary target molecule of bortezomib, proteasome subunit beta, type 5 (PSMB5), was not detected in the tumour cells in any of the cases but showed an abundant expression in cells in the microenvironment. However, the deubiquitinases (DUBs) of the proteasome, the ubiquitin carboxyl‐terminal hydrolase L5 (UCHL5) and the ubiquitin specific peptidase 14 (USP14), were detected in the cytoplasm of the tumour cells in 77% and 74% of the cases, respectively. The adhesion regulating molecule 1 (ADRM1) was detected in 98% of the cases. There was no correlation between the expression of any of the studied markers and clinical outcome or GC/non‐GC phenotype.
Conclusions
We suggest that UCHL5 and/or USP14 should be further evaluated as new targets for proteasome inhibitors in DLBCL. The lack of expression of PSMB5 on the tumour cells might provide an explanation of the relatively poor results of bortezomib in DLBCL.
Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a ...physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have ...helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning–based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML.
•Progression of AML is associated with pro-inflammatory mediators through altered expression levels of CR1, DPEP1, IL1R1, and ST18.•Upregulated CD6 and downregulated INSR are nodes in gene expression networks linked to AML relapse, according to machine learning analysis.
Display omitted
To evaluate the prognostic value of the cell of origin (COO) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBLC), prospectively treated by rituximab, dexamethasone, high-dose ...cytarabine, and cisplatin (R-DHAP) versus rituximab, ifosfamide, carboplatin, and etoposide and followed by intensive therapy plus autologous stem-cell transplantation on the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial.
Among the 396 patients included on the trial, histologic material was available for a total of 249 patients at diagnosis (n = 189 patients) and/or at relapse (n = 147 patients), which included 87 matched pairs. The patient data were analyzed by immunochemistry for CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by fluorescent in situ hybridization for BCL2, BCL6 and c-MYC breakpoints. The correlation with survival data was performed by using the log-rank test and the Cox model.
Characteristics of immunophenotype and chromosomal abnormalities were statistically highly concordant in the matched biopsies. In univariate analysis, the presence of c-MYC gene rearrangement was the only parameter to be significantly correlated with a worse progression-free survival (PFS; P = .02) and a worse overall survival (P = .04). When treatment interaction was tested, the germinal center B (GCB) -like DLBCL that was based on the algorithm by Hans was significantly associated with a better PFS in the R-DHAP arm. In multivariate analysis, independent prognostic relevance was found for the GCB/non-GCB the Hans phenotype interaction treatment (P = .04), prior rituximab exposure (P = .0052), secondary age-adjusted International Prognostic Index (P = .039), and FoxP1 expression (P = .047). Confirmation was obtained by gene expression profiling in a subset of 39 patients.
COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.
PDF
