scholarly journals Histone Modifications in Development and Malignancy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-49-SCI-49
Author(s):  
Elisa Oricchio
Keyword(s):  
Structural Changes ◽  
Conflicts Of Interest ◽  
Epigenetic Modification ◽  
Chromosomal Alterations ◽  
Multiple Tumor ◽  
Non Hodgkin Lymphoma ◽  
New Therapeutic Approaches ◽  
Chromatin Interactions ◽  
Transcriptional Changes ◽  
Chromosomal Amplifications

Non-Hodgkin lymphoma (NHL) development is driven by the accumulations of multiple genetic, epigenetic, and chromosomal alterations. These lesions can lead to modifications of the chromatin architecture. To identify novel oncogenic interactions driven by modifications of the chromatin 3D organization, we combined high-throughput chromatin conformation capture data (Hi-C) in lymphoma cells with whole genome sequencing (WGS) and epigenetic and transcriptional profiles of primary patient samples and cell lines. Recently, we found that a significant interplay exists between the compartmentalization of the genome into topologically associating domains (TADs) and epigenetic and transcriptional changes mediated by mutated EZH2. Indeed, EZH2 mutations drive aberrant increase of H3K27me3 within specific TADs, resulting in loss of promoter-promoter interactions, synergistic silencing of multiple tumor suppressors and, thus, increased B-cell proliferation and tumor aggressiveness1. Now, we are further investigating how chromosomal amplifications and translocations forms new long-range interactions between enhancers and promoters to support oncogene expression. Importantly, we observed that epigenetic editing of enhancers and pharmacological depletion of H3K27Ac reduces the number of interactions between specific enhancers and promoters and this loss of interactions directly affects gene expression and cell differentiation. These results indicate that is possible to block the oncogenic effect of chromosomal alterations by targeting epigenetic modification in enhancer regions and preventing the formation of oncogenic chromatin interactions. Overall, our results demonstrate that it is important to contextualize the effects of genomic alterations in the 3D organization of the chromatin, to uncover new oncogenic mechanisms and improve the design of new therapeutic approaches. Donaldson-Collier MC, Sungalee S, Zufferey M, et al. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat Genet. 2019;51(3):517. doi:10.1038/s41588-018-0338-y Disclosures No relevant conflicts of interest to declare.

scholarly journals Arrhythmogenic Cardiomyopathy: Molecular Insights for Improved Therapeutic Design

2020 ◽  
Vol 7 (2) ◽  
pp. 21 ◽  
Author(s):  
Tyler L. Stevens ◽  
Michael J. Wallace ◽  
Mona El Refaey ◽  
Jason D. Roberts ◽  
Sara N. Koenig ◽  
...  
Keyword(s):  
Structural Changes ◽  
Mendelian Inheritance ◽  
In Vivo Studies ◽  
Arrhythmogenic Cardiomyopathy ◽  
New Therapeutic Approaches ◽  
Increased Risk ◽  
Fatty Replacement ◽  
Mechanistic Basis

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by structural and electrical cardiac abnormalities, including myocardial fibro-fatty replacement. Its pathological ventricular substrate predisposes subjects to an increased risk of sudden cardiac death (SCD). ACM is a notorious cause of SCD in young athletes, and exercise has been documented to accelerate its progression. Although the genetic culprits are not exclusively limited to the intercalated disc, the majority of ACM-linked variants reside within desmosomal genes and are transmitted via Mendelian inheritance patterns; however, penetrance is highly variable. Its natural history features an initial “concealed phase” that results in patients being vulnerable to malignant arrhythmias prior to the onset of structural changes. Lack of effective therapies that target its pathophysiology renders management of patients challenging due to its progressive nature, and has highlighted a critical need to improve our understanding of its underlying mechanistic basis. In vitro and in vivo studies have begun to unravel the molecular consequences associated with disease causing variants, including altered Wnt/β-catenin signaling. Characterization of ACM mouse models has facilitated the evaluation of new therapeutic approaches. Improved molecular insight into the condition promises to usher in novel forms of therapy that will lead to improved care at the clinical bedside.

scholarly journals Epigenetic regulation of human papillomavirus transcription in the productive virus life cycle

2020 ◽  
Vol 42 (2) ◽  
pp. 159-171 ◽  
Author(s):  
Megan Burley ◽  
Sally Roberts ◽  
Joanna L. Parish
Keyword(s):  
Life Cycle ◽  
Host Cell ◽  
Epigenetic Regulation ◽  
Epigenetic Modification ◽  
Large Family ◽  
Human Papillomaviruses ◽  
Early Gene ◽  
Virus Transcription ◽  
Chromatin Interactions ◽  
Virus Life Cycle

AbstractHuman papillomaviruses (HPV) are a large family of viruses which contain a circular, double-stranded DNA genome of approximately 8000 base pairs. The viral DNA is chromatinized by the recruitment of cellular histones which are subject to host cell–mediated post-translational epigenetic modification recognized as an important mechanism of virus transcription regulation. The HPV life cycle is dependent on the terminal differentiation of the target cell within epithelia—the keratinocyte. The virus life cycle begins in the undifferentiated basal compartment of epithelia where the viral chromatin is maintained in an epigenetically repressed state, stabilized by distal chromatin interactions between the viral enhancer and early gene region. Migration of the infected keratinocyte towards the surface of the epithelium induces cellular differentiation which disrupts chromatin looping and stimulates epigenetic remodelling of the viral chromatin. These epigenetic changes result in enhanced virus transcription and activation of the virus late promoter facilitating transcription of the viral capsid proteins. In this review article, we discuss the complexity of virus- and host-cell-mediated epigenetic regulation of virus transcription with a specific focus on differentiation-dependent remodelling of viral chromatin during the HPV life cycle.

Cooperation of MLL/AF10(OM-LZ) with K-Ras Mutation Induced Myeloid Sarcoma in a Mouse Bone Marrow Transplantation Model.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1964-1964
Author(s):  
Jen-Fen Fu ◽  
Lee-Yung Shih
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Flow Cytometric Analysis ◽  
Myeloid Sarcoma ◽  
Mouse Bone Marrow ◽  
Myeloproliferative Disease ◽  
Multiple Tumor

Abstract Abstract 1964 Poster Board I-987 We analyzed genetic mutations in a large cohort of AML patients and found that two of the five patients with MLL/AF10 and N-/K-RAS mutations had cutaneous tumors (myeloid sarcomas). To study the cooperative role of MLL/AF10 and N-/K-RAS in the formation of myeloid sarcoma, we established two cell lines by retroviral transduction of MLL/AF10(OM-LZ) and K-RASG12C into GFP-B6 mouse bone marrow cells. Flow cytometric analysis revealed that the cells with MLL/AF10(OM-LZ) and K-RASG12C showed a decreased Mac-1 and CD115 expression when compared with the cells with a single MLL/AF10(OM-LZ) mutation. Microarray and RT-PCR analyses revealed an increased gene expression in Hoxa10 and Meis1, but not Hoxa9. In addition, the phagocytosis related genes, Cybb and Lyz were decreased in the cells harboring MLL/AF10(OM-LZ) and K-RASG12C. These results suggested that cooperation of MLL/AF10(OM-LZ) and K-RASG12C mutations blocked the cells in a more primitive hematopoietic stage. When the two cell lines were intra-peritoneally injected into B6 mice, the mice developed myeloproliferative disease-like myeloid leukemia as that of the mice transplanted with cells carrying a single MLL/AF10(OM-LZ) fusion gene. The median survival time were 33±4.2 and 31.6±5.1 days, respectively, which were shorter than that of the mice transplanted with cells carrying a single MLL/AF10(OM-LZ) fusion gene (49.8±5.0 days). We found that the majority (84%) of mice transplanted with cells harboring both MLL/AF10(OM-LZ) and K-RASG12C mutations formed multiple tumor masses involving gastrointestinal tract, kidney, peritoneum, paraspinal soft tissue, and/or skin. Cytological examination from the imprint smears of tumor masses showed massive infiltrates of leukemia blastic cells. Immunohistochemical stains of the paraffin-fixed histological sections of tumor masses were positive for GFP, confirmed that the tumor cells were generated from the transplanted cell lines. We have established a mouse model which can be used for further study of the myeloid sarcoma formation. Disclosures: No relevant conflicts of interest to declare.

Relapsed Childhood High Hyperdiploid Acute Lymphoblastic Leukemia: Genome-Wide Screening Reveals the Presence of Preleukemic Ancestral Clones and the Secondary Nature of Microdeletions and RTK-RAS Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2591-2591
Author(s):  
Josef Davidsson ◽  
Kajsa Paulsson ◽  
David Lindgren ◽  
Henrik Lilljebjörn ◽  
Tracy Chaplin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Structural Changes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Snp Array ◽  
Prognostic Impact ◽  
Genetic Changes ◽  
Ras Mutations ◽  
Paired Samples

Abstract Abstract 2591 Poster Board II-567 Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% relapse. This makes it important to identify these patients already at diagnosis to ensure proper risk-stratification. To identify changes associated with relapse and ascertain the genetic evolution patterns, SNP array and mutation analyses of FLT3, KRAS, NRAS, and PTPN11 were performed on 11 paired diagnostic/relapse samples. The “triples trisomies” +4, +10, and +17 were detected in 64%, a frequency similar to the one generally observed at diagnosis, thus questioning their favorable prognostic impact. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. Based on the genetic relationship between the paired samples, three groups were delineated: 1) identical genetic changes at diagnosis and relapse (18%), 2) clonal evolution with all changes at diagnosis being present at relapse (18%), and 3) clonal evolution with some changes conserved, lost or gained (64%), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern and perhaps necessary for overt leukemia. Disclosures: No relevant conflicts of interest to declare.

Association of Hodgkin Lymphoma and Non-Hodgkin Lymphoma In the Same Patient. Clinicopathologic Characteristics and Outcome In a Series of 20 Cases

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3886-3886
Author(s):  
Stefano Fogazzi ◽  
Alessandra Tucci ◽  
Chiara Bottelli ◽  
Marco Ungari ◽  
Fabio Facchetti ◽  
...  
Keyword(s):  
T Cell ◽  
Hodgkin Lymphoma ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Stage Iii ◽  
Classical Type ◽  
Composite Lymphoma ◽  
Histologic Subtype ◽  
Non Hodgkin Lymphoma ◽  
Systemic Symptoms

Abstract Abstract 3886 The possibility that a non-Hodgkin lymphoma (NHL) is diagnosed either simultaneously or at a different time in patients with Hodgkin lymphoma (HL) has been reported both as single case reports and in small series. However the significance of such an association is still unclear. We searched the database of HL consecutively diagnosed at our Institution in order to identify such cases and to detect any specific clinicopathological or prognostic characteristics. Twenty cases were retrieved representing to our knowledge the largest series reported so far. Fifteen of them were diagnosed over the last ten years and represented 4,6% of the 326 cases of HL diagnosed during the same time period. There were 12 males and 8 females. Median age was 58. It was lower in patients developing HL as the first lymphoma (35 vs 65). HL was diagnosed first in 7 cases and as the second lymphoma in 9 cases. The mean interval between the two diagnoses was longer when HL occurred first (112 vs 60 months). In four patients the two diagnoses were made simultaneously, on the same histologic specimen in two. Histologic diagnoses of NHL included diffuse large B cell in 6, T cell lymphoma in 4 (peripheral unspecified 2, cutaneous 2), follicular in 3, marginal in 3 and lymphocytic in 4 cases each. T cell, marginal and lymphocytic lymphoma were overrepresented in comparison with their general frequency among NHL. No differences emerged regarding the timing of NHL occurrence, except for lymphocytic lymphoma which never occurred after HL. Nodular sclerosis was the most frequent histologic subtype of HL, representing 58% of cases, whereas only two cases (10%) were nodular lymphocyte predominance HL (NLPHL). Immunohistochemistry on Reed Sternberg cells of HL classical type showed CD30+ in 16 (100%) and CD15+ in 10 (63%) of 16 evaluable cases. CD20+ was present in 3/14 classical HL (21%) and in the 2 cases of NLPHL. Clinical presentation of HL was more aggressive than expected with no patient in stage I, 60% of patients in advanced stage (stage II: 8, stage III: 6; stage IV: 6) and 50% with systemic symptoms. There were no differences between cases presenting as first or second lymphoma. Among NHL 15 cases presented in stage III/IV and 6 with systemic symptoms. In seven cases autoimmune abnormalities/disease coexisted, including Raynaud, thyroiditis, cutaneous lupus, and vasculitis. HL patients were treated with ABVD in 11 cases, or with other chemotherapy programs +/− radiotherapy. NHL received treatments according to histology. In composite lymphoma treatment was directed against the more aggressive lymphoma. In spite of the unfavourable presentation, the complete response rate (CRR) in HL was 74% and the overall response rate (ORR) 79%. It was worse (5/8: 63%) when HL presented after NHL. In NHL the CRR was 63% and the ORR 95%. Relapse occurred in 2 HL, in one composite lymphoma (HL+FL > DLBCL) and in 5 NHL. Seven patients died, with active disease in 6 (2 HL, 4 NHL). One patient died of lung cancer. With a median follow up of 6 years, the 5-year and 10-year survival are 83,5% +/−9% and 68%+/−12%, respectively. We conclude that the occurrence of HL and NHL in the same patient is not rare. T-cell, marginal and lymphocytic lymphoma seem to be more frequently associated with HL. Pathologic and immunohistochemical characteristics are otherwise not distinctive. Patients present with advanced disease and systemic symptoms but their response to treatment and overall prognosis seem not worse than that of patients affected by HL as single tumour. The selective association between some histologic types of NHL and HL as well as the possible association with autoimmunity warrants further investigation. Disclosures: No relevant conflicts of interest to declare.

Gemcitabine, Dexamethasone and Cisplatin (GDP regimen) As First Salvage Treatment of Patients with Refractory or Relapsed Diffuse large B Cell Non Hodgkin Lymphoma (DLBCL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2696-2696
Author(s):  
Thoraya Mohamed Abdel Hamid ◽  
Mona fawzy Ramadan ◽  
Abeer Bahnassy ◽  
Fouad Abu- Taleb ◽  
Magdy Saber
Keyword(s):  
Conflicts Of Interest ◽  
High Dose ◽  
Chemotherapy Response ◽  
Non Hodgkin Lymphoma ◽  
Study Results ◽  
Significant Difference ◽  
Duration Of Response ◽  
Relapsed Disease ◽  
Time To Relapse

Abstract Abstract 2696 Background: Many chemotherapy regimens have been used for patients with refractory or relapsed DLBCL. No regimen has demonstrated superiority to another in this setting. Specific markers could predict the response to certain agents. Aim: to evaluate the response of GDP regimen in relapsed and refractory DLBCL patients and to assess ribonucleotide reductase subunit M1 (RRM1) as a possible predictor marker to Gemcitabine response. Patients and method: Patients with Relapsed or refractory DLBCL after one previous anthracycline-containing chemotherapy regimen were treated with the GDP regimen. RRM1 was assessed by immunohistochemistry in 55 cases and its expression was correlated to treatment outcome. Patients who could not proceed to stem cell transplantation (SCT) were followed for chemotherapy response and their results are presented. Results: The study included 70 patients with a median age of 40 years (range 18–73). At start of GDP, 19 patients (27.1%) were refractory and 51 (72.9%) were relapsed. After 4 cycles of treatment, 42 patients achieved CR, with a CR rate of 60% (95% CI: 53–68%). The median DFS was 6 months (95% CI: 5 to7 months), this DFS didn't include patients who underwent auto SCT. After a median follow-up of 20 months (range 6 to 30 months), the median OS of the patients who achieved CR was not reached, while those who didn't achieve CR had a median OS of 27.4 months (p= 0.01). Correlation between response and the pretreatment prognostic factors including IPI score or any of its elements, previous line of chemotherapy, time to relapse and status at time of salvage were studied with only significant difference in response to GDP between patients with refractory and those with relapsed disease (CR= 21.1% versus 60% respectively, p < 0.001). There was significant correlation between RRMI study results and response to GDP, 30/31 cases with low RRM1 expression achieved CR (96.8%), while only 7/24 cases with high expression achieved CR (29.2%), (p=0.001). No significant relation could be found between RRM1 expression and DFS. Conclusion: GDP regimen is active for patients with refractory or relapsed DLBCL however, the duration of response is short and high-dose therapy with SCT support is the reference postremission treatment. RRM1expression can predict response to Gemcitabine-based chemotherapy. Disclosures: No relevant conflicts of interest to declare.

The Prevalence of HIV-1 DNA in AIDS-Related Lymphoma throughout the Epidemic in the US

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5205-5205
Author(s):  
Leanne C Huysentruyt ◽  
Lawrence D Kaplan ◽  
Michael S. McGrath
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
Conflicts Of Interest ◽  
Kaposi Sarcoma ◽  
Sequence Evolution ◽  
Genomic Amplification ◽  
Hiv Dna ◽  
Non Hodgkin Lymphoma ◽  
Highly Active ◽  
Reported Data ◽  
Hiv 1

Abstract Abstract 5205 Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) are the two most common AIDS-defining cancers and significantly contribute to HIV-related deaths. While highly active antiretroviral therapy (HAART) has produce a sharp decline in the incidence of KS and AIDS-related NHL (ARL), HIV-infected patients are still at a high risk for developing these malignancies. Recent studies evaluating HIV-1 DNA in 91 AIDS-related KS cases demonstrated a significant decrease in the prevalence of HIV-1 DNA positive KS cases post-HAART (after 1996; 16.7%) as compared to pre-HAART (before 1996; 45%) corresponding to the decrease in incidence of this cancer since the introduction of HAART. Additionally HIV was more prevalent in sites of visceral KS (51.9%) as compared to skin KS (30.7%). We have recently evaluated the HIV sequence evolution in the context of metastatic ARL and identified lymphoma-specific HIV compartmentalized within tumor sites that was genetically distinct from HIV in non-tumor sites suggesting a specific form of HIV arises within individuals who develop ARL. The goal of this research was to determine the prevalence and quantity of HIV DNA in 119 ARL biopsies representing the entire span of the HIV epidemic (1982–2005). Whole genomic amplification was performed on DNA extracted from three 10um paraffin embedded tissue sections and the presence of HIV-1 DNA was determined by quantitative amplification of the HIV gag gene. Of the 119 cases, 45% contained detectable levels of HIV DNA. The HIV antigen was predominantly localized to macrophages. A subset of the ARL cases in this study contained approximately 1 HIV copy per cell which is extremely high considering previously reported data describing HIV-infected lymph nodes contained approximately 1 HIV copy per 1000 cells. Similar to what was observed for KS, the prevalence of HIV-positive ARLs has decreased in the post-HAART era (39%) when compared to pre-HAART (54%). While the prevalence of HIV-1 DNA positive ARLs declined in the post-HAART era, it was not to the same extent as what was observed for KS. Thus, our data is consistent with a decrease in the incidence of both tumor types in the post-HAART era. The higher prevalence of HIV-1 DNA in visceral sites of KS and lymphoma specific-HIV sequences in sites of metastatic lymphoma suggests that HIV, especially HIV infected macrophages, may play a role in the pathogenesis of KS and ARL disease progression. Disclosures: No relevant conflicts of interest to declare.

DNMT3A mutations Predict for Inferior Outcome in NPM1-Wildtype and Molecular Unfavorable Cytogenetically-Normal Acute Myeloid Leukemia: A Study of the German-Austrian AMLSG

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 415-415 ◽  
Author(s):  
Verena I. Gaidzik ◽  
Richard F. Schlenk ◽  
Peter Paschka ◽  
Anja Stölzle ◽  
Andrea Corbacioglu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Epigenetic Modification ◽  
Methylation Status ◽  
Prognostic Impact ◽  
Sequencing Analysis ◽  
Mutational Status ◽  
Acute Myeloid

Abstract Abstract 415 Background: Alteration of DNA methylation, a hallmark of epigenetic modification, is currently discussed as one important pathomechanism in leukemogenesis. Using a next-generation sequencing approach, a frameshift mutation of the gene encoding the DNA methyltransferase (DNMT3A) in an acute myeloid leukemia (AML) case was identified. DNMT3A catalyses the addition of a methyl group to the cytosine residue of CpG dinucleotides, thereby affecting promoter methylation status and gene expression. Subsequent sequencing analysis in an independent cohort of 288 AML patients (pts) revealed DNMT3A mutations (DNMT3Amut) in 22% of the pts; mutations were associated with intermediate-risk cytogenetics and poor outcome. Aims: To evaluate frequency and clinical impact of DNMT3Amut in pts with AML aged 18 to 61 years who were treated within AMLSG treatment trials AML HD98A (Schlenk et al., J Clin Oncol 2010;28:4642–8) and AMLSG 07–04 (NCT00151242). Methods: DNMT3A mutation analysis was performed in 1218 AML (HD98A, n=685; AMLSG 07–04, n=533; de novo AML, n=1102; s-AML, n=45; t-AML, n=69) using a DNA-based PCR assay for all coding exons (1 to 23) followed by direct sequencing. The median follow-up was 5.06 years. Results: DNMT3A mut were found with an overall frequency of 19.6% (239/1218); 189 mutations were located in the MTase domain clustering at amino acid R882 (79%). All but one mutation were heterozygous; only 4 cases had two mutations. DNMT3A sequence alterations included 17 frameshift, 4 nonsense, and 222 missense mutations. DNMT3A mut pts were significantly older (P=.01), more frequently females (P=.001), had higher white blood cell and platelet counts (both P<.0001), and higher bone marrow blasts percentage (P=.001). DNMT3Amut were associated with cytogenetically-normal AML (CN-AML, P<.0001), while DNMT3Amut were rare in favorable and adverse-risk karyotypes (P<.0001). Correlations with other molecular markers (NPM1, CEBPA, FLT3, IDH1/2, TET2, ASXL1) revealed a significant association with NPM1 (P<.0001), FLT3-ITD (P<.0001), and IDH1/2 (IDH1R132, P<.0001; IDH2R140, P=.0003; IDH2R172, P=.03) mutations, while co-occurrence of CEBPA (P=.02) and ASXL1 (P=.02) mutations was less frequent. DNMT3A mutational status did not impact complete remission (CR) rate, event-free (EFS) and relapse-free survival (RFS), neither in the whole cohort (P=.09, P=.98, P=.11; respectively) nor in the subgroup of CN-AML (P=.39, P=.79, P=.19, respectively). DNMT3Amut had a negative impact on overall survival (OS) in trend in the whole cohort (P=.07) and significantly in CN-AML (P=.02). In multivariable analyses, DNMT3Amut were in trend associated with a negative prognostic impact on OS (hazard ratio, 1.24; P=.06). In addition, we performed subgroup analyses according to (1) the NPM1 mutational status, and (2) the molecular risk groups of CN-AML (as defined by the European LeukemiaNet classification). DNMT3Amut did not impact OS in NPM1-mutated patients in the whole cohort as well as in CN-AML (P=.34; P=.22; respectively), while in NPM1-wildtype patients DNMT3Amut were associated with inferior OS in both, the whole cohort and in CN-AML (P=.001; P=.005; respectively). In molecular unfavorable CN-AML (NPM1-wildtype with or without FLT3-ITD, NPM1-mutated with FLT3-ITD, CEBPA-wildtype), DNMT3Amut were significantly associated with worse OS (P=.002) compared with DNMT3A-wildtype pts, even outweighing FLT3-ITD as an unfavorable prognostic marker. There was no effect of DNMT3Amut in molecular favorable-risk CN-AML. Conclusions: DNMT3A mutations are confirmed as frequent genetic aberrations in AML, associated with normal karyotype, NPM1, FLT3-ITD, and IDH1/2 mutations. DNMT3Amut predicts for inferior outcome in molecularly-defined subsets of AML, that is, NPM1-wildtype AML and molecular unfavorable CN-AML. As a single marker, DNMT3Amut only had a moderate effect on outcome. Disclosures: No relevant conflicts of interest to declare.

Fludarabine, Mitoxantrone and Rituximab (FMR) Regimen in Previously Untreated Patients with Indolent Non-Hodgkin Lymphoma: Efficacy, Safety and PET Data On 285 Patients.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2736-2736
Author(s):  
Pier Luigi Zinzani ◽  
Cinzia Pellegrini ◽  
Enrico Derenzini ◽  
Alessandro Broccoli ◽  
Letizia Gandolfi ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Bone Marrow Involvement ◽  
Stage Ii ◽  
Hematologic Toxicity ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Significant Difference ◽  
Grade 3

Abstract Abstract 2736 In this retrospective single-center study we aimed at evaluating the efficacy and safety of fludarabine, mitoxantrone and rituximab (FMR) regimen as first line therapy in untreated patients with follicular non-Hodgkin lymphoma (NHL) and indolent non-follicular NHL considering also the role of positron emission tomography (PET) after this chemo-immunotherapy induction as predictor of survival. Between January 2000 and May 2011, 285 patients with stage II-IV untreated indolent follicular (excluding grade IIIb) NHL (n=142) and indolent non-follicular (including marginal zone lymphoma, MZL [n=111] and small lymphocytic lymphoma, SLL [n=31]) NHL (n=143) were diagnosed and treated at our institution in the outpatient clinic. Median age was 63 years (range, 25–83 years) and the median time from diagnosis to study entry was 3 months (range, 1–5 months). 20 patients had stage II, 75 patients had stage III, and 190 had stage IV disease (155 patients had bone marrow involvement). Standard fludarabine (25 mg/m2 iv on days 2, 3 and 4), mitoxantrone (10 mg/m2 iv on day 2) and rituximab (375 mg/m2 iv on day 1) were given every 28 days for six cycles. Globally, after FMR regimen, the overall response rate (ORR) was 83.2%, including a 71.6% complete remission (CR) rate (204 patients) and a 11.6% partial remission (PR) rate (33 patients). According to the histology, in the follicular subset, the ORR was 81.1% with a CR rate of 69.2% while in the indolent non-follicular subset the ORR was 85.2% with a CR rate of 73.9%. In particular, in the indolent non-follicular NHL subgroup the CR rate was 80.2% in MZLs and 51.6% in SLLs, respectively. Toxicities were generally mild and mainly hematologic. Overall 88 (30.8%) patients had grade ≥3 hematologic toxicity, and 26 (9.1%) patients had non-hematologic toxicity with 3 cases of grade ≥3 (1 neurologic toxicity and 2 hepatic toxicity). In terms of secondary malignancies, only 3 (1.0%) hematologic neoplasms were reported (1 myelodisplastic syndrome after 9 months from the end of the treatment and 2 acute lymphoblastic leukemia after 8 and 11 months from the end of the treatment, respectively). Globally with a median follow up of 40 months (range, 12–144 months), at 11 years the overall survival (OS) was 78.8%, the disease-free survival (DFS) was 73.4% (with only 29 relapses), and the progression-free survival (PFS) was 71.9%. Regarding the comparison between the two subsets, follicular vs indolent non-follicular, no statistically significant differences were observed in OS, DFS and PFS curves. Furthermore, a sub-sample of 132 patients (75 follicular NHLs and 57 indolent non-follicular NHLs) had a PET evaluation before the treatment (staging) and 4 to 6 weeks after completion of the sixth cycle of chemo-immunotherapy (restaging, final PET [f-PET]). Post-induction PET-positive patients had a significantly inferior OS at 6 years: 71.4% compared with 98.4% for f-PET-negative patients (p<0.0001, Figure 1a). In terms of PFS at 6 years, there was not a statistically significant difference among f-PET-positive patients and f-PET-negative patients (Figure 1b). Figure 1a. Figure 1a. Figure 1b. Figure 1b. In conclusion, this study suggests and confirms that FMR is a very active, well tolerated (in terms of acute and long-term side effects) chemo-immunotherapy front-line treatment for follicular NHL and indolent non-follicular NHL. PET status at the end of this chemo-immunotherapy induction is quite controversial as a predictor of survival. Disclosures: No relevant conflicts of interest to declare.

DNMT3A Mutation Leads to Hematopoietic Dysregulation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2382-2382
Author(s):  
Jie Xu ◽  
Wei-na Zhang ◽  
Tao Zhen ◽  
Yang Li ◽  
Jing-yi Shi ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Epigenetic Modification ◽  
Hematopoietic Cells ◽  
In Vitro Assays ◽  
Clinical Samples ◽  
Hematopoietic Stem

Abstract Abstract 2382 Epigenetic modification process is required for the development of hematopoietic cells. DNA methyltransferase DNMT3A, responsible for de novo DNA methylation, was newly reported to have a high frequency of mutations in hematopoietic malignancies. Conditional knock-out of DNMT3A promoted self-renewal activity of murine hematopoietic stem cells (HSCs). However, the role of mutated DNMT3A in hematopoiesis and its regulative mechanism of epigenetic network mostly remain unknown. Here we showed that the Arg882His (R882H) hotspot locus on DNMT3A impaired the normal function of this enzyme and resulted in an abnormal increase of primitive hematopoietic cells. In both controlled in vivo and in vitro assays, we found that the cells transfected by R882H mutant promoted cell proliferation, while decreased the differentiation of myeloid lineage compared to those with wild type. Analysis of bone marrow (BM) cells from mice transduced by R882H reveals an expansion of Lin−Sca-1+C-kit+ populations and a reduction of mature myeloid cells. Meanwhile, a cluster of upregulated genes and downregulated lineage-specific differentiation genes associated with hematopoiesis were discovered in mice BM cells with R882H mutation. We further evaluated the association of mutated DNMT3A and HOXB4 which was previously detected to be highly expressed in clinical samples carrying R882 mutation. Compared with wildtype DNMT3A, R882H mutation disrupted the repression of HOXB4 by largely recruiting tri-methylated histone 3 lysine 4 (H3K4). Taken together, our results showed that R882H mutation disturbed HSC activity through H3K4 tri-methylation, and transcriptional activation of HSC-related genes. Disclosures: No relevant conflicts of interest to declare.

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