Peripheral blood cells from 28 patients with leukemic cutaneous T-cell lymphoma including 25 patients with Sézary syndrome were evaluated for expression of regulatory T-cell-associated markers (FoxP3, CD25, CTLA-4, neurophilin-1), T-cell activation markers (CD28 and its ligands B7.1 and B7.2) and NK cell-associated markers (NKG2D and its ligands MicA and Mic-B) using real-time quantitative polymerase chain reaction. T-plastin served as a positive genetic marker, and its expression correlated to blood tumor burden. More than 90% of samples had transcripts for CD28 and Mic-B, but less than 30% of samples expressed FoxP3, CTLA-4 and CD25. Expression of Mic-B by neoplastic cells could provide another mechanism to inhibit anti-tumor immune responses. FoxP3 expression correlated with a poor prognosis. Although the underlying mechanisms accounting for this correlation remain unclear, the expression of the Foxp3 and CTLA-4 regulatory elements indicates that a subset of leukemic cases displays a regulatory T-cell phenotype.
Lymphoma; Sézary syndrome; T-plastin; FoxP3; Mic-B; CD28; regulatory T-cell
This study evaluated if measures of psychological well-being, including coping style are associated with advance care planning (ACP). Data were from the HEMA-COMM study, a prospective observational study of physician-patient communication in patients with hematologic malignancies. ACP was defined as having a living will, having a health care proxy, discussing life support with family or friends, and discussing life support with a doctor or nurse. 293 patients participated: only 45 (15%) had all the elements of ACP, 215 (73%) had at least 1 element of ACP, while 33 (11%) did not engage in ACP. In multivariate analysis, specific coping styles but not other measures of psychosocial well being were associated with having written ACP. Verbal ACP was associated with patient-reported health and physician estimate of life expectancy. Our study suggests that tailoring ACP discussions to a patient’s coping style may increase engagement in ACP.
Advance care planning; Coping; Health Status; Hematological Cancer
Peripheral T-cell (PTCL) and NK cell lymphomas have poor survival with conventional cytotoxic chemotherapy. Because angiogenesis plays an important role in the biology of PTCL, a fully humanized anti-VEGF antibody, bevacizumab (A), was studied in combination with standard CHOP chemotherapy (ACHOP) to evaluate its potential to improve outcome in these patients.
Patients were treated with 6–8 cycles of ACHOP followed by 8 doses of maintenance A (15 mg/kg every 21 days). 46 patients were enrolled on this phase 2 study from July 2006 through March 2009. 44 patients were evaluable for toxicity and 39 were evaluable for response, progression and survival.
A total of 324 cycles (range: 2–16, median 7) were administered to 39 evaluable patients and only 9 completed all planned treatment. The overall response rate was 90% with 19 (49%) CR/CRu, 16 (41%) PR. The 1-year progression free survival (PFS) rate was 44% at a median follow-up of 3 years. The median PFS and overall survival (OS) rates were 7.7 and 22 months, respectively. Twenty-three patients died (21 from lymphoma, 2 while in remission). Grade 3 or 4 toxicities included febrile neutropenia (n=8), anemia (n=3), thrombocytopenia (n=5), congestive heart failure (n= 4), venous thrombosis (n=3), gastrointestinal hemorrhage /perforation (n=2), infection (n=8), and fatigue (n=6). Despite a high overall response rate, the ACHOP regimen failed to result in durable remissions and was associated with significant toxicities. Studies of novel therapeutics are needed for this patient population, whose clinical outcome remains poor.
Lymphoma and Hodgkin disease; Chemotherapeutic approaches; Immunotherapeutic approaches
Patients with multiple myeloma who are refractory or intolerant to both bortezomib and lenalidomide have a poor prognosis. Next-generation therapies carfilzomib and pomalidomide have shown promising activity in this dual refractory population. Here we describe the clinical characteristics and ascertain the effects of carfilzomib and pomalidomide on survival in this patient cohort. We retrospectively reviewed the records of 65 dual refractory/intolerant myeloma patients diagnosed between January 2007 and May 2012 at a single institution. The median overall survival (OS) from the time patients became dual refractory/intolerant was 10.2 months. Patients who received carfilzomib or pomalidomide after they became dual refractory/intolerant had a better OS compared to those who did not (12.6 vs. 6.8 months, p=0.03 by Wilcoxon test). Prospective randomized control trials are needed for confirmation.
multiple myeloma; lenalidomide; bortezomib; pomalidomide; carfilzomib
Deregulated JAK2 signaling plays an important role in the pathogenesis of myeloproliferative neoplasms (MPN). We and others have shown constitutive activation of JAK2 and STAT3 in diffuse large B cell lymphomas (DLBCL). We sought to determine the mechanism of JAK2 signaling in DLBCL tumors with a genetic approach. The most common JAK2 activating mutation present in most MPNs is V617F (exon 14 within the pseudokinase-domain); however, this mutation is absent in lymphoid malignancies. We bi-directionally sequenced all the domains of the JAK2 gene and performed mutational analysis. No novel non-synonymous mutations were detected in the 40 DLBCL tumors tested. However synonymous and non-synonymous single nucleotide polymorphism (SNPs) were detected within the exons 6, 9 and 19 in the majority of patients. Taken together, these data suggest that other mechanisms for altered JAK2 signaling aside from activating JAK2 mutations are present in DLBCL. Targeting JAK2 activation could be an important therapeutic target for DLBCL. Indeed, the JAK2 inhibitor ruxolitinib is now approved for the treatment of MPN. Our study indicates that JAK2 targeted clinical trials in lymphoma should not be confined to only JAK2 mutation cases but rather based on pathway activation.
extramedullary; relapse; allogeneic transplantation; AML; acute myelogenous leukemia
Overexpression of zeta-chain-associated protein 70 (ZAP-70) was recently recognized as an independent prognostic marker for the aggressive form of chronic lymphocytic leukemia (CLL). The objective of this study was to demonstrate the feasibility and implementation of quantitative detection of ZAP-70 protein in B cells to clearly distinguish patients with CLL with the aggressive form of the disease. B cells were isolated from patient blood and lysed. Released ZAP-70 protein was detected using an immunomagnetic fluorescence assay. The assay protocol was developed using Jurkat cells and recombinant ZAP-70 (rZAP-70). The limit of detection was determined to be lower than 125 Jurkat cells and 39 pg of rZAP-70 protein. The signal response was linear over a wide dynamic range, from 125 to 40 000 Jurkat cells per test (R2 = 0.9987) and from 0 to 40 000 pg rZAP-70 protein per test (R2 = 0.9928). The results from 20 patients with CLL correlated strongly with flow cytometry analysis. Concordance between the two methods for positive and negative results was 100% (7/7) and 92% (12/13), respectively, while the overall concordance between the two methods was 95%. The assay reported here is a simple, reliable and reproducible method for quantitative detection of ZAP-70 in patient leukemic cells, without the need for cell fixation or permeabilization. The ZAP-70 signal was linear over a wide dynamic range, which we believe enables quantitative assessment of small changes in ZAP-70 expression over the course of the disease and in response to therapeutic intervention.
Chronic lymphocytic leukemia (CLL); ZAP-70; flow cytometry; immunomagnetic fluorescence assay; Signalyte-II spectrofluorometer
Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.
Myeloma; IMiDs; cereblon
The risk from cumulative erythrocyte transfusions is poorly understood in oncology populations. This analysis among long-term survivors explored variation in transfusional burden over progressive eras of treatment identifying those at risk for iron overload. Transfusion records of 982 survivors of hematological malignancies treated at St. Jude were reviewed. After exclusions, 881 (90%) were assessed for cumulative volume, weight-adjusted volume, and transfusion number. Treatment intensity was assigned using the ITR-3 scale. Hematopoietic stem cell transplant and acute myeloid leukemia survivors had greater transfusional burden than conventional therapy recipients and acute lymphoblastic leukemia survivors respectively. Survivors of 5-10 years were more likely than survivors of >10 years to receive ≥10 transfusions (OR=2.0, 95% CI 1.5-2.8). Those with higher ITR-3 scores and more recent decades of treatment had a higher transfusional burden. Comprehensive transfusion histories are useful in identifying those at highest risk for iron overload.
Transfusion medicine; Iron Overload; Cancer survivors; Pediatric leukemia
Between 2005 and 2008, we conducted separate phase II clinical testing of 3 distinct anti-VEGF therapies for patients with relapsed/refractory CLL. Collectively, 46 patients were accrued to trials of single-agent anti-VEGF antibody (bevacizumab, n=13) or 1 of 2 receptor tyrosine kinase inhibitors (AZD2171, n=15; sunitinib malate, n=18). All patients have completed treatment. Patients received a median of 2 cycles of bevacizumab, AZD2171, or sunitinib malate. All 3 trials were closed early due to lack of efficacy. No complete or partial remissions were observed. Individually and collectively, these studies indicate single-agent anti-VEGF therapy has minimal clinical activity for patients with relapsed/refractory CLL.
chronic lymphocytic leukemia; angiogenesis; vascular endothelial growth factor (VEGF); therapy; bevacizumab; receptor tyrosine kinase inhibitor
We enrolled 28 eligible patients with relapsed chronic lymphocytic leukemia (CLL) to a phase II study of single agent thalidomide (200 mg/d, with dose escalation up to 1000 mg/d over 60 days). The median age was 66 years and 71% were males. Study participants received a median of 2 (range 1–7) prior treatment regimens and 61% had Rai stage 3–4 disease at enrollment. Grade 3 or higher hematologic toxicity was observed in 13 (46%) and 16 (57%) had grade 3 or higher non-hematologic toxicity. Grade 3–4 tumor flare was observed in five (18%) patients. The overall response rate was 11% (3 of 28) with one (4%) complete remission and two (7%) partial remissions. Duration of response for these three responders was 3, 14 and 15 months. Fourteen (50%) patients had stabilisation of disease for a median duration of 8 months (95% CI: 7–16 months). Median time to progression for all 28 patients was 7.3 months. Although thalidomide appears to have modest clinical activity in pretreated/relapsed CLL primarily based on reduction of the absolute lymphocyte count, in our opinion the toxicity profile precludes it from more active investigation in CLL.
CLL; treatment; relapsed; thalidomide; angiogenesis
Philadelphia chromosome-positive (Ph+) AML is a controversial diagnosis,
as others propose it represents CML in blast phase (CML-BP).
NPM1 mutations occur in 25-35% of AML but are absent in CML
patients. Conversely, ABL1 mutations occur in 25% of
Imatinib-naïve CML-BP but are not described in AML patients. We analyzed
for NPM1 and ABL1 mutations in 9 Ph+ AML and 5
CML-BP patients initially presented in BP. In 6 Ph+ AML cases, we screened for a
panel of gene mutations using Sequenome®-based methods including
AKT1, AKT2, AKT3, BRAF,
EGFR, GNAQ, GNAS,
IDH1, IDH2, KRAS,
MET, NRAS, PIK3CA, and
RET. Two of 9 (22%) Ph+ AML patients had
NPM1 mutations and were alive 36 and 71 months after
diagnosis. All Ph+ AML were negative for ABL1 and other gene
mutations. One (20%) CML-BP patients had ABL1 mutation; no
patients had NPM1 mutations. These data suggest that Ph+ AML is
distinct from CML-BP.
acute myeloid leukemia; BCR-ABL1; blast phase; chronic myelogenous leukemia; NPM1; Philadelphia chromosome
Improved medical care could have altered the clinical presentation and survival of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) complicated by autoimmune cytopenia (AID cytopenia). We reviewed the clinical characteristics, treatment, and outcome of AID cytopenia that was diagnosed in 75 (4.3%) of 1750 CLL patients seen at a single institution over 10 years. Compared to historical reported data, our study shows a lower rate of autoimmune hemolytic anemia (2.3%), and similar rates of immune thrombocytopenia (2.0%) and pure red blood cell aplasia (0.5%). AID cytopenia occurred at all stages of CLL, responded well to treatment, did not alter overall survival, and contributed to death in only 6 (12%) patients. We propose that more sensitive and accurate diagnostic methods for CLL have decreased the perceived prevalence of AID cytopenia and that improvements in management could have increased the survival of these patients.
We previously reported that 18F-fluorodeoxyglucose positron emission tomography scan (FDG-PET) is almost universally positive in patients with T cell lymphoma. In the present analysis we examined the impact of FDG-PET on the initial staging of peripheral T cell lymphomas (PTCLs), and the prognostic value of interim FDG-PET. This retrospective analysis identified patients with mature T or natural killer (NK) lymphomas who had PET scans as part of initial staging or staging at relapse [(n = 95) (staging cohort)] in the PTCL database at Memorial Sloan-Kettering Cancer Center. A subset of these patients had repeat PET for interim restaging during initial therapy with curative intent [(n = 50) (interim restaging cohort)]. The frequency of specific T cell histologies included in this analysis were: PTCL not otherwise specified (NOS) (n = 35); angioimmunoblastic T cell lymphoma (AITL) (n = 17); anaplastic large cell lymphoma (ALCL), ALK-1+ (n = 11) and ALK-1− (n = 12); adult T cell lymphoma/leukemia (ATLL) (n = 7); NK/T cell lymphoma (NKTCL) (n = 10); and enteropathy-associated T cell lymphoma (EATL) (n = 3). In the staging cohort, 77 patients were newly diagnosed, and 18 had relapsed disease. Pretreatment FDG-PET was positive in 96% of patients. PET identified additional disease sites in 47/95 patients (50%) when added to conventional staging. Most frequently identified additional sites were: other nodal (n = 24); bone (n = 10); skin (n = 8); nasopharynx (n = 4); spleen (n = 3); and lung (n = 2). However, FDG-PET modified computed tomography (CT)-based staging in only 5/95 patients (5.2%): two patients were upstaged and three patients were downstaged. FDG-PET-based staging did not alter planned treatment for any patient. Interim restaging with PET was performed after a median of 4 cycles of chemotherapy. In this cohort, treatment regimens included cyclophosphamide, doxorubicin, vincristine and prednisone CHOP (n = 19); CHOP/ifosfamide, carboplatin and etoposide (ICE) (n = 26); and other (n = 7). Subsequently, 29 patients were consolidated with either autologous (n = 22) or allogeneic (n = 7) stem cell transplant. After a median follow-up of 3.4 years for surviving patients, those with negative interim PET had superior progression-free survival (PFS) compared to patients with positive interim PET (p = 0.03). There were no differences in overall survival (OS). In PTCL, FDG-PET commonly identifies additional sites of disease but infrequently impacts CT-based staging and does not influence therapy. Interim FDG-PET may predict for PFS. FDG-PET should be integrated into prospective trials to confirm these findings.
Lymphoma and Hodgkin disease; FDG-PET; T cell lymphoma; prognosis; staging
Statins and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications. In vitro studies suggest that statins and NSAIDs may have potential as anti-cancer therapies in low grade non-Hodgkin lymphomas including chronic lymphocytic leukemia (CLL) and a recent observational study found statin use was associated with improved event free survival in patients with follicular lymphoma. Other studies have suggested that statins reduce the efficacy of rituximab by inhibiting binding to CD20. We therefore conducted an observational cohort study of 686 patients with newly diagnosed Rai stage 0 CLL to evaluate whether statin or NSAID use was related to their clinical outcome or influenced the efficacy of rituximab therapy. At diagnosis, 136 (20%) patients took statins and 230 (34%) scheduled daily aspirin, ibuprofen, or naproxen. No difference in time to treatment was observed based on statin or NSAID use. Among patients receiving a rituximab containing first-line therapy, no difference in time to salvage treatment was observed based on statin use. Although previous studies suggested statins may improve event free survival among patients with follicular lymphoma, we find no impact of statins on time to initial therapy in this large study of patients with Rai stage 0 CLL. The in vitro observation that statins reduce rituximab efficacy does not appear to have clinical significance in CLL care.
Antibiotic variation among pediatric oncology patients has not been well-described. Identification of significant variability in antibiotic use within this population would warrant evaluation of its clinical impact. We conducted a retrospective cohort study of newly diagnosed patients with pediatric acute lymophoblastic leukemia (ALL) hospitalized from 1999 to 2009 in 39 freestanding US children’s hospitals within the Pediatric Health Information System. Medication use data were obtained for the first 30 days from each patient’s index ALL admission date. Antibiotic exposure rates were reported as antibiotic days/1000 hospital days. Unadjusted composite broad-spectrum antibiotic exposure rates varied from 577 to 1628 antibiotic days/1000 hospital days. This wide range of antibiotic exposure was unaffected by adjustment for age, gender, race and days of severe illness (adjusted range: 532–1635 days of antibiotic therapy/1000 hospital days). Antibiotic use for children with newly diagnosed ALL varies widely across children’s hospitals and is not explained by demographics or illness severity.
Leukemia; pediatrics; benchmarking; drug resistance; microbial
The aim of this study was to learn the toxicity and efficacy of adding 4 doses of rituximab to a standard platinum-based salvage regimen for relapsed CD20+ B-cell non-Hodgkin lymphoma. Patients were treated with rituximab 375 mg/m2 days 1,8,15, 22 (cycle 1 only); cisplatin 100 mg/m2 over 24 h on day 3, cytosine arabinoside 2 g/m2 IV every 12 h × two doses on day 4, dexamethasone 40 mg PO/IV days 3–6, and G-CSF days 5–14. The ORR was 82% (47/57) with 33% (19/57) complete remissions and 49% (28/57) partial remissions. The duration of response (DR) for the 47 responders was 10.5 months (95% CI: 5.3–16.8). The median time to progression (TTP) was 10.3 months (95% CI: 5.3–14.0), the median event-free survival (EFS) was 5.3 months (95% CI: 3.9–11.0), and the median overall survival was 30.5 months (95% CI: 17.8–60.6). We conclude that rituximab can be safely added to standard DHAP.
Non-Hodgkin lymphoma; salvage chemotherapy; transplant; rituximab
The optimal dose and schedule of thymoglobulin (ATG) for graft-versus-host disease prevention (GVHD) is unknown. We compared two doses of ATG (4.5 mg/kg and 7.5 mg/kg) in a Bayesian adaptively randomized fashion, and assessed whether ATG levels measured on days 0, 7, 14, and 28 were associated with clinical outcomes. Treatment success was defined as the patient being alive, engrafted, in remission, and without acute GVHD at day 100. Twenty patients received ATG 4.5 mg/kg (n=15) or 7.5 mg/kg (n=5) with reduced-intensity conditioning (RIC) followed by unrelated donor hematopoietic cell transplantation (HCT). The first 10 patients were randomized fairly. Then, based on data from the first 10 patients, the posterior probability that the 4.5 mg/kg dose is superior to the 7.5 mg/kg dose was found to be 0.94, and the next 10 patients were each assigned to the ATG 4.5 mg/kg arm. The posterior mean treatment success rates for the ATG 4.5 mg/kg and ATG 7.5 mg/kg arms were 0.73 and 0.45, respectively. The posterior probability that the success rate was greater in the 4.5 mg/kg arm than in the 7.5 mg/kg arm was 0.93. There was no difference in the overall survival (p=0.607), relapse-free survival (p=0.607), treatment-related mortality (p=0.131), or incidence of acute (p=0.303) or chronic GVHD (p=0.999) between the two doses. ATG levels were not associated with clinical outcomes. Thus, our results favor the use of ATG 4.5 mg/kg over ATG 7.5 mg/kg in patients undergoing unrelated donor HCT with RIC regimens.
ATG; Graft-Versus-Host Disease; hematopoietic cell transplantation
Treatment options for older patients with acute myeloid leukemia (AML) and for patients with relapsed/refractory AML are limited, and outcomes are poor. Decitabine, a hypomethylating agent, is active in patients with myelodysplastic syndrome (MDS) and AML, but its optimal dose and schedule are unknown. We report the efficacy and safety of repeated 10-day cycles of decitabine 20 mg/m2 administered intravenously over 1 h in 52 newly diagnosed and 102 relapsed/refractory patients. Repeated 10-day cycles of decitabine produced a complete response (CR) in 40% of newly diagnosed older patients with AML, many of whom had adverse prognostic features. The median overall survival (OS) was 318 days but there was prolonged survival in responders of 481 days. Relapsed/refractory patients had a CR rate of 15.7% with a median OS of 177 days. Extramedullary toxicity was mild and the regimen was well tolerated for ongoing post-remission, outpatient maintenance cycles. Responses were durable for over 1 year.
Leukemia; myeloid; acute; drug therapy; treatment outcome; induction chemotherapy/methods
Splenectomy may be an effective therapeutic option for treating massive splenomegaly in patients with myeloproliferative neoplasms (MPNs). There is still limited data on its short- and long-term benefits and risks.
Efficacy and short-term complications were analyzed in 94 patients with different MPNs who underwent splenectomy at MD Anderson. The long-term impact of splenectomy on overall survival (OS) and transformation free survival (TFS) was evaluated in 461 patients with myelofibrosis (MF) seen at MD Anderson including 50 who underwent splenectomy during disease evolution.
Splenectomy improved anemia and thrombocytopenia in 47% and 66% of patients, respectively. Most common complications were leukocytosis (76%), thrombocytosis (43%), and venous thromboembolism (16%). Post-operative mortality was 5%. Among patients with MF, splenectomy during disease evolution was associated with decreased OS (Hazard Ratio [HR] =2.17, p<0.0001) and TFS (HR=2.17, p<0.0001). This effect was independent of the Dynamic International Prognostic Scoring System.
Splenectomy is a possible therapeutic option for patients with MF and other MPNs, and its greatest benefits are related to improvement in spleen pain and discomfort, anemia and thrombocytopenia. However, in patients with MF it appears to be associated with increased mortality.
Myelofibrosis; Myeloproliferative Neoplasms; Splenectomy; Survival; Acute Myeloid Leukemia
Hematopoietic stem cell transplantation (HSCT) is a promising treatment for lymphomas. Its success depends on effective pre-transplant conditioning regimens. We previously reported on the efficacy of DNA alkylating agent-nucleoside analog (NA) combinations for conditioning in AML. We hypothesized that a similar combinatory approach can be used for lymphomas. A combination of busulfan (Bu) with two NAs – clofarabine (Clo), fludarabine (Flu) or gemcitabine (Gem) – resulted in synergistic cytotoxicity in lymphoma cell lines. We demonstrated that the [2 NAs+Bu] combination activates a DNA damage response through the ATM-CHK2 and ATM-CHK1 pathways, leading to cell cycle checkpoint activation and apoptosis. Histone modifications and KAP1 phosphorylation are indicative of chromatin relaxation mediated by the nucleoside analogs which sequentially increase Bu alkylation. Addition of suberoylanilide hydroxamic acid (SAHA) enhanced chromatin relaxation through increased histone acetylation and further augmented the cytotoxicity of [2 NAs+Bu]. Our results provide a preclinical basis for a clinical trial on using [2 NAs+Bu±SAHA] combinations as conditioning therapy for chemotherapy-refractory lymphoma patients undergoing HSCT.
DNA alkylating agent; busulfan; clofarabine; gemcitabine; SAHA; lymphoma
Disturbances of circadian rhythms and mammalian clock genes have been implicated in the etiologies of many chronic illnesses, including cancer. We show that transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha)-regulated PER2 activation is a potential tumor suppressor pathway in diffuse large B-cell lymphoma (DLBCL), one of the commonest types of mature B-cell lymphoma. Expression analysis of human B-cell lymphoma samples including DLBCL (n = 50), mantle cell (n = 21), follicular (n = 25) and Burkitt (n = 18) lymphoma revealed markedly down-regulated CEBPA and PER2 mRNA levels exclusively in DLBCL samples compared to control lymphatic tissue. We demonstrated direct regulation of the circadian core clock gene PER2 by C/EBPalpha in the pro-B cell line Ba/F3, and forced expression of PER2 resulted in decreased proliferation, GO/G1 cell cycle arrest and increased rates of apoptosis. Interestingly, treatment of human DLBCL cell lines with the histone deacetylase-inhibitor suberoylanilide hydroxamic acid (SAHA) significantly increased the expression of C/EBPalpha and Per2, accompanied by cell growth inhibition; in contrast, siRNA knockdown of CEBPA reduced the anti-proliferative effect of SAHA treatment. Our results show for the first time that C/EBPalpha with its associated direct core clock gene target, PER2, are highly deregulated in DLBCL, suggesting an important tumor suppressive pathway in the pathogenesis of this lymphoma entity.
Transcription factor; circadian rhythm; mature B-cell lymphoma
Ionizing radiation increases risk for acute leukemia, but less is known about radiation and risk of other hematologic malignancies such as non-Hodgkin lymphoma (NHL). We compared second primary NHL incidence among patients who did and did not receive initial radiotherapy for first primary solid malignancy during 1981-2007 reported in nine SEER population-based cancer registries. We identified 5,590 second NHL cases among 1,450,962 one-year cancer survivors. NHL risk was increased after initial radiotherapy for all solid cancers combined (multivariate Poisson regression relative risk [RR]:1.13, 95% confidence interval [CI]:1.06-1.20), non-small cell lung cancer (RR:1.53, 95%CI:1.08-2.17), and prostate cancer (RR:1.19, 95%CI:1.09-1.32). NHL risk increased with longer latency after radiotherapy for non-small cell lung cancer (ptrend=0.003) but decreased for prostate cancer (ptrend=0.017). There was no clear NHL risk pattern by NHL subtype or age. Our study provides limited evidence that radiotherapy for solid malignancy is associated with increased risk of subsequent NHL.
second malignancies; radiotherapy; non-Hodgkin lymphoma