Abnormalities Of FAM46C, AHCYL1, CDC14A and CDKN2C Genes Located At Chromosome 1p Detected By QM-FISH Identifies Deletion Of 1p32.3 Covered CDKN2C Is An Independent Adverse Prognostic Marker In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3145-3145
Author(s):  
Fei Li ◽  
Li-ping Hu ◽  
FengYan Jin ◽  
Yan Xu ◽  
Gang An ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Artificial Chromosome ◽  
Chromosome 1 ◽  
Chromosome 1P ◽  
Large Size ◽  
1P Deletion ◽  
The Impact

Abstract SNP arrays and FISH showed Chromosome 1 appeared as a critical region in MM pathogenesis and was associated with adverse survival, such as: 1q gain and 1p deletion. Recent years, some studies found deletions of some genes in the common minimum deletion regions on 1p were related to adverse prognosis, such as FAM46C at 1p12, CDC14A at 1p21.2, CDKN2C at 1p32.3. However, these studies were limited to one or two regions and lacked the comparison among the effects of different sites on prognosis. The characteristics of chromosome 1p abnormalities are not clear and no uniform consensus has been obtained that which locus is the best prognostic factor suitable for clinical routine detection. In addition, there's lack of data on the impact of 1p abnormalities on homogeneous group of patients. We investigated the abnormalities of FAM46C, AHCYL1, CDC14A, CDKN2C genes located at chromosome 1p12, 1p13.3, 1p21.2 and 1p32.3 by quantitative multicolor-fluorescence in situ hybridization (QM-FISH) using bacterial artificial chromosome (BAC) clones in 230 previously untreated myeloma patients. FAM46C, AHCYL1, CDC14A, CDKN2C genes were labeled with Green-dUTP (green), promoFluor-555-aadUTP (orange), PF590-dUTP (Red) and PF415-dUTP (Blue) and used as a FISH probe. The results demonstrated the deletion rates of 1p12, 1p13.3, 1p21.2 and 1p32.3 were 13.0%, 18.7%, 20.8% and 9.06% respectively. The deletion rate of 1p was 24.2%. Amplifications of 1p with 3.04%, 2.60%, 3.77% and 4.15% respectively in 1p12, 1p13.3, 1p21.2 and 1p32.3 were detected in some patients. These amplifications were significant lower than those of deletions (P=0.000, 0.000, 0.000, 0.021). Interestingly, we found chromosome 1p abnormalities were complex, various in forms. Among 57 patients with del(1p), 26.3% of patients presented with one locus deletion, 22.8% with two loci loss, 35.1% with three loci loss, 15.8% with four loci loss. Most (73.7%) of del (1p) were large size of deletion (≥ two regions). Del (1p) was positively correlated with high LDH (≥220U/L) (P=0.026), del (13q14) (P=0.023), and high percentage of plasma cells in bone Marrow (≥ 50%) (P=0.001). 108 patients were homogeneously treated with thalidomide-based chemotherapy (TAD/MPT). Survival analysis showed the median progression-free survival (PFS) of patients with and without del (1p) were 13.0 vs.26 months (P=0.002), median overall survival (OS) were 15.5 vs. 39.5 months (P=0.000). In addition, we found patients with sole del (1p) involving 1p12 or/and 1p13 had no worse prognosis. Patients with del (1p32.3) had shorter PFS (9.0 vs. 23.0, P=0.001) and OS (9.0 vs. 39.0, P=0.000). In multivariate analyses, 1p32.3 deletion appeared as an independent negative prognostic factor regarding to complex karyotype, LDH≥220U/L and del (17p13) in thalidomide-based chemotherapy group. Hazard ratio showed that the progression risk and death risk in patients with 1p32.3 were increased 5.64 (P=0.031) and 8.314 times respectively (P=0.011). Conclusion our datas show that chromosome 1p abnormalities are complex, various in forms, mainly with large size of deletion, rarely amplification. 1p deletions are negative prognostic factors for PFS and OS in MM patients receiving thalidomide-based chemotherapy. 1p32.3 deletion is the most important 1p deletion and is an independent poor factor. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Excess Serine from the Microenvironment Caused the Impaired Megakaryopoiesis and Thrombocytopia in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4331-4331
Author(s):  
Chunmei Kuang ◽  
Meijuan Xia ◽  
Gang An ◽  
Cuicui Liu ◽  
Dan Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Mouse Model ◽  
Disease Progression ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Major Complication ◽  
Progression Free Survival ◽  
Erythroid Progenitors

Background: Thrombocytopenia is major complication in a subset of patients with multiple myeloma (MM). However, a lack of detailed studies about the megakaryopoiesis, thrombopoiesis as well as their connections with the survival of patients limits us to explore whether thrombocytopenia could be used as a reliable prognostic factor for MM. Materials and Methods: In this study, 1393 newly diagnosed MM patients were selected for investigating the potential connection between PLT counts and clinical characteristics including ISS stage, overall survival as well as progression free survival. Besides, 5T33MMvt-KaLwRij mouse model were also used to examine the megakaryopoiesis and thrombopoiesis during disease progression. The proportion and function of different subpopulations of cells including megakaryocytes, megakaryocytic-erythroid progenitors (MEPs), common myeloid progenitors (CMPs) and Lin-Sca-1+c-kit+ (LSK) cells were measured both in MM patients and mouse models. Gas chromatography-time-of-flight mass spectrometry (GC-TOFMS)-based metabolomics was used to analyze the metabolites. Results: Of the 1393 studied patients, 298 cases of MM patients are found with thrombocytopenia at the time of diagnosis. PLT counts were lower both in stage Ⅱ (P<0.01) and Ⅲ patients (P<0.001) than stageⅠpatients. Interesting, we found MM patients with thrombocytopenia had a significantly lower OS (P<0.001) and PFS (P<0.001). In mouse model, we also found PLT counts gradually decreased in peripheral blood during the disease progression (P<0.001). Further analysis demonstrated the proportion and the absolute numbers of megakaryocytes and MEPs were diminished both in mouse and MM patients with thrombocytopenia. PLT counts were negative correlated with the percentage of plasma cells or IgG2b levels (P<0.001), suggesting a potential connection of malignant cells infiltration and thrombocytopenia. In mechanism, metabolomics analysis with BM plasma identified 16 differential metabolites in MM patients with thrombopoiesis (VIP > 1.2, P < 0.05). Among them, serine was observed significantly be elevated in MM mouse and suffice to inhibit the megakaryopoieis and thrombopoiesis in vitro. Conclusion: PLT counts might be used as a reliable prognostic factor for MM patients since the thrombocytopenia was associated with poor survival in MM patients. The thrombocytopenia in MM might attribute to, at least partially, the inhibition by serine from the microenvironment. Our findings revealed novel mechanism of MM and might eventually shed light on the treatment of MM patients. Disclosures No relevant conflicts of interest to declare.

KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial

2009 ◽  
Vol 27 (35) ◽  
pp. 5931-5937 ◽  
Author(s):  
Susan D. Richman ◽  
Matthew T. Seymour ◽  
Philip Chambers ◽  
Faye Elliott ◽  
Catherine L. Daly ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Braf Mutation ◽  
Poor Prognosis ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Poor Prognostic Factor ◽  
Minimal Impact ◽  
The Impact

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) in CLL: First Results of An EBMT Randomized Trial Comparing Autotransplant Versus Wait and Watch.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 877-877
Author(s):  
Mauricette Michallet ◽  
Peter Dreger ◽  
Laurent Sutton ◽  
Ronald Brand ◽  
Sue Richards ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Disease Status ◽  
Primary Objective ◽  
Phase Iii ◽  
Induction Treatment ◽  
Hematopoietic Stem ◽  
Binet Stage ◽  
The Impact

Abstract Abstract 877 This phase-III randomized EBMT-intergroup trial studied the impact of a consolidating autoHSCT vs no consolidation for patients with CLL in Binet stage A progressive, B or C , in CR, nodular PR or VGPR after first or second line therapy. The primary objective was to show that autoHSCT increased the 5-year progression-free survival (PFS) by 30%. Although it had been calculated that 270 patients were to be randomized, the study was terminated by the steering committee in July 2007 due to poor accrual. Here we present a first analysis based on 69% of expected follow-up forms. Results: Between November 2001 and July 2007, 223 patients were enrolled (SFGM-TC/FCLLG n=98, MRC n=62, GCLLSG n=32, SAKK n=10, other EBMT centers n=17). There were 74% males and 26% females. Binet stages were progressive A 13%, B 67%, C 20%; 59% were in CR, and 41% in very good or nodular PR. Of note, SFGM-TC/FCLLG included only patients in CR. 82% of the patients were enrolled in 1st, and 18% in 2nd remission. Patients were randomized between group 1 (autoHSCT n=112) and group 2 (observation n=111) after an induction treatment which was left at the discretion of the investigators. Median PFS was 43 months in the observation group but not reached in the autoHSCT group; 5-year PFS was 48% and 65%, respectively (p=0.005). Accordingly, autoHSCT halved the relapse risk (5-year relapse incidence 25% vs. 51%; HR 0.4 [0.23-0.71], p=0.002). Cox modeling for randomization arm, Binet stage, disease status, line of treatment, contributing group (country), and the interaction between randomization arm and contributing group confirmed that autoHSCT significantly improved PFS (HR 0.41 [0.23-0.75] p=0.004). The beneficial effect of autoHSCT was stable over all contributing groups although patients accrued by SFGM-TC/FCLLG overall had a significantly better PFS than patients from other countries (HR 0.2 [0.08-0.55], p=0.001). At 5 years, the probability of OS was 92% and 91% for autoHSCT and observation, respectively. Significant differences in terms of non-relapse death were not observed. At the last follow up, among 205 evaluable patients, 186 are alive (147CR, 39 relapse), 19 died (14 from relapse and 5 from non-relapse causes) . In conclusion, in patients with CLL in first or second remission, consolidating autoHSCT reduces the risk of progression (PFS) by more than 50%, but has no effect on overall survival. Disclosures: No relevant conflicts of interest to declare.

Outcome of Patients with Relapsed/Refractory AIDS-Related Lymphoma In the AIDS Malignancy Consortium (AMC) 1997–2008

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3569-3569
Author(s):  
Ariela Noy ◽  
Ulas Darda Bayraktar ◽  
Neel Gupta ◽  
Adam M. Petrich ◽  
Page Moore ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Infectious Complications ◽  
High Dose ◽  
Hiv Diagnosis ◽  
Curative Intent ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Aids Related Lymphoma

Abstract Abstract 3569 Introduction: High dose therapy (tx) with autologous hematopoietic stem cell transplantation (AHSCT) in (rel/rfr) lymphoma is the standard of care in the general population with chemosensitive disease. The feasibility of second line therapies (Tx) and AHSCT in (rel/rfr) AIDS related lymphoma (ARL) has been shown in a number of trials. However, the true impact of 2nd line tx and AHSCT is unknown, as nearly all studies focus on those already with disease sensitive to 2nd therapy going onto transplantation. The only recent study capturing patients (n=50) before 2nd line tx showed 49% progression-free survival (Re et al. Blood 2009). Here, we retrospectively analyzed the outcome of patients (pts) presenting at 13 US AIDS Malignancy Consortium sites with (rel/rfr) ARL in the HAART era. Patients and Methods: HIV-positive pts initiating tx for (rel/rfr) ARL between 1997–2008 were included. Overall survival (OS) was calculated from the initiation of 2nd line tx. Results: A total of 126 pts received 2nd line tx. Only those 88 pts who received 2nd line with curative intent to treat (ITT) were included in the analysis. Baseline and selected clinical characteristics are summarized in the table. Median CD4 at HIV diagnosis was 110 (n=37) with a range of 12 to 1000. At ARL dx, median CD4 was 152 (5-803). 47% had an opportunistic infection (OI) prior to ARL. 2nd line tx were: ICE (n=34), EPOCH (n=16), ESHAP (n=11), High-dose MTX variants (n=10), Hodgkin's specific tx (n=5), DHAP (n=4) and others (n=8). Thirty-two (36%) had a response to 2nd line tx (CR, n=21; PR, n=11). Of 50 pts with grade ≥3 toxicities, the most common were thrombocytopenia (46%) and neutropenic fever (44%). Six pts died during 2nd line tx due to infectious complications, with 1 aspergillosis. Best response to 2nd line tx: Thus, CR/PR was 32/88 (36%) in ITT analysis. Only 10/32 CR/PR pts went onto AHSCT due to availability and changing treatment paradigms. Conditioning was BEAM (n=9) and Bu/Cy (n=7). No pt went onto allotransplant. At AHSCT day +90, 10 pts were in CR. For all pts, median follow-up was 122 weeks (range, 8–597), median OS was 38 weeks (95% CI, 27–63). Reflecting the 65% prevalence of pts refractory to 2nd line tx in the non-AHSCT group, OS was longer in pts who underwent AHSCT compared to those who did not (2-year OS: 55.3% vs. 31.0%). Surprisingly, 1-year OS in the CR/PR pts was 87.5±12.5% for AHSCT and 81.8±8.2% for non-AHSCT. One Burkitt pt survived a year without AHSCT. Discussion: Rel/rfr ARL was treated aggressively in this largest ever reported cohort, but CR/PR was only 32/88 (36%) in ITT analysis. Not all CR/PR pts went onto AHSCT due to changing treatment paradigms and regional availability. Aggressive 2nd line tx and ASHCT was feasible despite prior low CD4 and OI, but DFS may be possible without transplant. We cannot draw conclusions about the impact of AHSCT from this retrospective cohort. Similarly, it is not known whether survival in (rel/rfr) ARLs is equivalent to the HIV negative population. The current paradigm is to offer pts with rel/rfr ARLs AHSCT if disease is chemosensitive and no contraindication exist. New strategies are needed for 2nd line therapy, particularly in rel/rfr BL. Disclosures: No relevant conflicts of interest to declare.

Plasmocytosis and Immunoparesis but Not Neutrophil to Lymphocyte Ratio Can Predict Time to Treatment in Smoldering Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5358-5358
Author(s):  
Alessandra Romano ◽  
Marzia L Consoli ◽  
Marina Parisi ◽  
Maide Cavalli ◽  
Nunziatina L Parrinello ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Complete Blood Count ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Bone Lesion ◽  
Progression Free Survival ◽  
Absolute Lymphocyte Count ◽  
Bone Lesions ◽  
Time To Treatment ◽  
Smoldering Myeloma

Abstract Objectives: We recently identified the ratio between absolute neutrophils count and absolute lymphocyte count, NLR ≥2, as a predictor of progression free survival (PFS) and overall survival (OS) in patients younger than 65 years with symptomatic Multiple Myeloma (MM). We retrospectively examined the NLR in a cohort of 140 smoldering Myeloma (sMM) defined accordingly to the updated IMWG 2014 guidelines accessed our Center between June 2006 and June 2014. Methods: NLR was calculated using data obtained from the complete blood count (CBC) at diagnosis and subsequently correlated with time to treatment (TTT) for symptomatic MM. All patients underwent bone marrow evaluation to estimate plasma cells infiltration (BMPC), Magnetic Resonance Imaging (MRI) to detect bone lesions, serum free-lite chain evaluation (sFLC) starting from January 2012 when they became evaluable in our center. Results: The mean NLR was 2.0 ± 0.1, lower than the value previously found for MM (2.7 ± 0.2, p= 0.005). Higher NLR was independent of BMPC amount, cytogenetics and sFLC. Using NLR ≥2 as predictive biomarker we could not predict TTT. In univariate analysis only BMPC ≥ 30% (p<0.0001), immunoparesis (suppression of one or more uninvolved immunoglobulins, p=0.017) and presence of at least one bone lesion at MRI (p<0.0001) could predict TTT. In multivariate analysis, these three parameters were independent (p<0.0001). Since new guidelines consider BMPC≥ 60% and positive MRI as myeloma-defining events, we proposed a simplified score model based on BMPC ≥ 30% (1 point) and immunoparesis (1 point). We identified patients with score 0 (20%) as low-risk (TTT at 60 months 0%), with score 1 (61%) as intermediate risk (TTT at 60 months 61%) and with score 2 as high-risk (TTT at 60 months 22%, p<0.0001). Conclusion: We confirmed BMPC and immunoparesis as strong predictors of outcome in sMM. Disclosures No relevant conflicts of interest to declare.

Loss of Heterozygosity 1p36 and 19q13 Is a Prognostic Factor for Overall Survival in Patients With Diffuse WHO Grade 2 Gliomas Treated Without Chemotherapy

2006 ◽  
Vol 24 (29) ◽  
pp. 4758-4763 ◽  
Author(s):  
Luigi Mariani ◽  
Gianluca Deiana ◽  
Erik Vassella ◽  
Ali-Reza Fathi ◽  
Christine Murtin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factor ◽  
Malignant Transformation ◽  
Loss Of Heterozygosity ◽  
Progression Free Survival ◽  
Who Grade ◽  
Free Survival ◽  
Extent Of Surgery ◽  
Oligodendroglial Component ◽  
The Impact

Purpose This study was conducted to elucidate the impact of loss of heterozygosity (LOH) for chromosomes 1p36 and 19q13 on the overall survival of patients with diffusely infiltrating WHO grade 2 gliomas treated without chemotherapy. Patients and Methods We assessed the LOH status of tumors from patients harboring WHO grade 2 gliomas diagnosed between 1991 and 2000. Patients were either followed after initial biopsy or treated by surgery and/or radiation therapy (RT). Overall survival, time to malignant transformation, and progression-free survival were last updated as of March 2005. Results Of a total of 79 patients, LOH 1p36 and LOH 19q13 could be assessed in 67 and 66 patients, respectively. The median follow-up after diagnosis was 6 years. Loss of either 1p or 19q, in particular codeletion(s) at both loci, was found to positively impact on both overall survival (log-rank P < .01), progression-free survival, and survival without malignant transformation (P < .05). Tumor volume (P < .0001), neurologic deficits at diagnosis (P < .01), involvement of more than one lobe (P < .01), and absence of an oligodendroglial component (P < .05) were also predictors of shorter overall survival. The extent of surgery was similar in patients with or without LOH 1p and/or 19q; RT was more frequently resorted to for patients without than for patients with LOH 1p/19q (30% v 60%). Conclusion The presence of LOH on either 1p36 or 19q13, and in particular codeletion of both loci is a strong, nontreatment-related, prognostic factor for overall survival in patients with diffusely infiltrating WHO grade 2 gliomas.

scholarly journals LSD1 Impairs the Epithelial-Mesenchymal Transition (EMT) and Osteoclastogenesis Potency in Multiple Myeloma and Synergistically Induces Cytotoxicity with HDAC Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3410-3410 ◽  
Author(s):  
Maria Gkotzamanidou ◽  
Mariateresa Fulciniti ◽  
Jesús Martín Sanchez ◽  
Mehmet Kemal Samur ◽  
Giovanni Parmigiani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Epithelial Mesenchymal Transition ◽  
Conflicts Of Interest ◽  
Hdac Inhibitors ◽  
Significant Inhibition ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Migration Assay ◽  
The Impact

Abstract Lysine-specific demethylase 1 (LSD1) is a FAD-dependent histone demethylase, which selectively removes mono- and di-methyl groups from histone 3 lysine 4 or 9 residues (H3K4, H3K9) leading to either repression or activation of transcriptome. Previous studies have shown that lenalidomide and pomalidomide cause cell cycle arrest in Multiple Myeloma (MM) by modifying the chromatin structure of the p21WAF-1 promoter through LSD1 demethylation. LSD1 forms a co-repression complex with HDAC1 and HDAC2, mSin3a, and MMSET. However, the functional role of LSD1 in MM and its contribution in aggressive traits of the disease is largely unknown. First, we evaluated the expression of LSD1 in different datasets of MM patients (GSE2113, GSE16122) and observed significant overexpression in patients with symptomatic MM and Plasma Cell Leukemia (PCL) (p<.001). The expression of LSD1 in a panel 45 HMCLs was also pronounced. We confirmed the expression and both its nuclear and cytoplasmic localization by immunoblotting analysis in 4 different HMCLs and primary bone marrow plasma cells from newly diagnosed, relapsed MM and PCL patients (N=8). We further evaluated the LSD1-mediated effect on proliferation and survival by performing loss- and gain of function studies. LSD1 knockdown in LP1 and MM1S cells resulted in modest cytotoxicity. After a combination silencing of JARID1 members and LSD1 we were able to observe a further significant decrease in survival of MM cells lacking JARID1C and LSD1, indicating that the overlapping demethylation of H3K4 is of high importance for the cell survival. We examined the post-translational histone modifications by immunobloting after LSD1 knockdown and as expected, we observed significant increase of K4me2/3 and K9me2 marks, but more interestingly, alteration of acetylation status of K9. Therefore, we performed cytotoxicity and proliferation experiments in MM after knockdown of LSD1 in combination with HDAC inhibitors (SAHA, LBH589) and we observed that LSD1 depletion enhances the cytotoxicity effect of HDACs inhibitors. LSD1 depletion resulted in significant reduction of mRNA levels by using real-time PCR and protein expression by immunoblotting of HDAC1 and HDAC2. Furthermore, based on findings of higher expression of LSD1 in more aggressive types of MM, we sought to investigate the impact of LSD1 in epithelial-mesenchymal transition (EMT). LSD1 depletion in MM1S and LP1 cells inhibited significantly the migratory ability estimated by transwell migration assay, invasion and wound healing assays. More importantly, MM cells lacking LSD1 expressed significant lower levels of E-cadherin, N-cadherin and Vimentin evaluated by immunoblotting and immunocytochemistry. We confirmed the suppression of EMT-involved gene expression by performing a PCR-microarray assay. Finally, given the presence of osteolytic lesions as a hallmark of disease, and consequent impact on outcome, we evaluated the impact of LSD1 on osteoblast differentiation and osteoclastogenesis. LSD1 depletion/ and pharmacological inhibition (S2101) resulted in significant inhibition of osteoclastogenesis and RANKL-induced resorption evaluated by double TRAP/ALP staining, survival of OCs, and mRNA expression level of osteoblast markers (APL, BSP, OC). In contrast, LSD1 overexpression confirmed the upregulation of Wnt/b-catenin pathway suggesting a possible underlying mechanism for the osteoclastogenesis potency in MM patients with high expression of LSD1. Taken together, our findings demonstrate a promising epigenetic approach in myeloma therapeutics by targeting the deregulated LSD1-methylome in MM patients earlier than aggressive disease phase. Disclosures No relevant conflicts of interest to declare.

Prognostic Relevance of Genomic Aberrations In Light Chain Only Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4036-4036
Author(s):  
Nan Jiang ◽  
Connie Qi ◽  
Young Trieu ◽  
Donna E. Reece ◽  
Hong Chang
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Prognostic Factor ◽  
Genetic Risk ◽  
Plasma Cells ◽  
Chromosome 1 ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Genetic Abnormalities ◽  
Genomic Aberrations

Abstract Abstract 4036 Background: Multiple myeloma (MM) is characterized by an expansion of clonal plasma cells with production of monoclonal immunoglobulin. The majority of MM patients produce an intact immunoglobulin, but in a subset of patients (≂f15%), the tumor produces monoclonal light chains only (LCO). Although specific genomic aberrations have emerged as a major prognostic factor in MM, the genomic changes and their prognostic impact on LCO myeloma patients are not clear. Methods: A total of 86 patients with LCO MM identified by urine and serum immunoelectrophoresis were included in this study. They were all uniformly treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT). The genomic risk factors including del(13q), del(17p), t(4;14), 1q21 gain and 1p loss– were evaluated by cytoplasmic fluorescence in situ hybridization (cIg-FISH) in clonal plasma cells and correlated with patients clinical outcomes. Results: cIg-FISH detected del(13q) in 41%, t(4;14) in 12%, del(17p) in18%, 1q21 gain in 25%, and 1p loss in 19% of the evaluable cases. In our entire cohort, the median post-transplant follow-up was 36.5 months with a median progression free survival (PFS) of 24.8 months [95% confidence interval (CI): 18.4–31.3] and overall survival (OS) of 68.8 months (95% CI: 50.2–87.5). Patients with del(13q) and 1q21 gains had a significantly shorter PFS (median 15.8 vs. 33.4 months, p=0.002; median 19.1 vs. 33.4 months, p=0.011, respectively), and shorter OS (median 56.2 vs. 80.4 months, p=0.021; median 26.9 vs. 77.9 months, p=0.006, respectively), than those without such genetic abnormalities. In addition, 1p loss was associated with a significantly shorter PFS (median 18.2 vs. 37.9 months, p=0.001). However, there was no significant difference in PFS or OS in patients with or without the high-risk genetic factors t(4;14) or del(17p). On multivariate analysis adjusting for all 5 genetic risk factors, del(13q) was an independent prognostic factor for PFS (p=0.011) and OS (p=0.045). Conclusion: Although LCO MM had a similar incidence of genetic abnormalities to common MM, only del(13q) and chromosome 1 abnormalities appear to adversely affect the survival in our cohort. Further larger, prospective studies are warranted to verify the role of these genomic aberrations in the genetic risk stratification of LCO MM. Disclosures: Reece: Celgene: Honoraria, Research Funding.

scholarly journals Expression of CRBN Signaling Pathway Proteins Assessed By Immunohistochemical Staining As Candidate Biomarkers for Outcome in Myeloma Patients Treated with IMiDs

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1909-1909
Author(s):  
Lijuan Chen ◽  
Qinglin Shi ◽  
Rong Wang ◽  
Xiupan Lu ◽  
Yan Gu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Signaling Pathway ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Expression Level ◽  
Positive Staining ◽  
Myeloma Cells ◽  
Low Level ◽  
First Line Therapy

Abstract Cereblon (CRBN), Ikaros (IKZF1), Aialos (IKZF3) and multiple myeloma oncogene 1 (MUM1) are important component of CRBN signaling pathway when treat MM cells with IMiDs. CRBN interacts with the DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B) and regulator of Cullins 1 (ROC1) to form the functional E3 ubiquitin ligase complex (E3ULC). CRBN increases the interaction between E3ULC and IKZF1/3, leading to increased ubiquitination degradation of IKZF1/3, and then induce cytotoxicity in myeloma cells. Subsequently, degradation of IKZF1/3 induce depression of multiple myeloma oncogene 1 (MUM1), which is also called interferon regulatory factors (IRF4) and proved to be involved in the anti-MM activity of IMIDs in previous studies. Immunohistochemical (IHC) staining may be a convenient approach for researchers to differentiate the myeloma cells and non-myeloma cells in BM samples. In this study, we evaluated CRBN, IKZF1/3 and MUM1 expression level in bone marrow (BM) by immunohistochemical (IHC) staining and investigated the relationship between expression level and treatment outcome after IMiDs-based or bortezomib-based therapy in 123 newly diagnosed multiple myeloma (NDMM) patients. H-score method was applied according to both intensity and extent of staining. The intensity was graded from 0 to 3("0"for absent staining, "1" for weak expression, "2" for intermediate expression, and "3" for strong expression of the protein). The extent was graded from "0" to "100" to represent the percentage of MM cells with positive staining of any intensity. H-score was obtained by multiplying the intensity and extent score, ranging from 0 to 300, which reflected protein expression level in MM cells. The median H-score of CRBN, IKZF1, IKZF3 and MUM1 were 200, 0, 180 and 180, respectively. According to the median H-score, we classified the patients into high or low expression group. One hundred and twenty-three NDMM patients were enrolled in this study, including 64 males (52.0%) and 59 females (48.0%). The median age was 60 years (range 34-84). Fifty-one patients (41.5%) received IMiDs-containing regimen as the first-line therapy. The median follow-up time was 24.0 months (range, 10-76 months). After treated with IMiDs, patients with high level of CRBN and MUM1 achieved better overall response rate (ORR) than those expressed low level (CRBN, 88.0% vs. 42.3%, P=0.001; MUM1, 83.3% vs. 48.1%, P=0.009). Besides, patients with CRBN and MUM1 overexpression also had better overall survival (median OS, CRBN, not reached vs. 21.0 months, P=0.004; MUM1, not reached vs. not reached, P=0.021) and progression free survival (median PFS, CRBN, 28.0 vs. 12.0 months, P=0.002; MUM1, 32.0 vs. 12.0 months, P<0.001) than patients with low level, as well as 2-year OS rate (CRBN, 86% vs. 44%, P=0.005; MUM1, 81% vs. 51%, P=0.003) and PFS rate (CRBN, 66% vs. 17%, P=0.001; MUM1, 63% vs. 20%, P<0.001). In addition, in high CRBN and MUM1 expression group, patients treated with IMiDs had a higher 2-year PFS rate than Bortezomib presentation (CRBN, 66% vs. 45%, P=0.004; MUM1, 63% vs. 36%, P=0.003). In low CRBN and MUM1 expression group, patients treated with IMiDs had an inferior OS (median OS, CRBN, 21.0 vs. 57.0 months, P=0.001; MUM1, not reached vs. 57.0 months, P<0.001) and PFS (median PFS, CRBN, 12.0 vs. 31.0 months, P=0.003; MUM1, 12.0 vs. 32.0 months, P<0.001) than patients with Bortezomib, as well as 2-year OS rate (CRBN, 44% vs. 91%, P=0.002; MUM1, 51% vs. 100%, P<0.001) and PFS rate (CRBN, 17% vs. 59%, P=0.010; MUM1, 20% vs. 68%, P<0.001). This study identified high levels of CRBN pathway proteins CRBN and MUM1 were correlated with favorable ORR and survival in NDMM patients with IMiDs therapy, also suggested that expression levels of CRBN signaling pathway proteins in plasma cells assessed by IHC staining could better direct clinic individualized therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long Term Survival Analysis of Multiple Myeloma Patients Receiving Induction Therapy+ Autologous STEM CELL Trasplantation, Comparing Velcade-Dexametasone to Alkylating Polichemotherapy As Induction Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5764-5764
Author(s):  
Sara Caceres ◽  
Rocio Cardesa ◽  
Carmen Cabrera ◽  
M. Helena Bañas ◽  
Fatima Ibañez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Conflicts Of Interest ◽  
Autologous Bone Marrow Transplantation ◽  
Young Patients ◽  
Progression Free Survival ◽  
Autologous Bone Marrow ◽  
Term Survival ◽  
The Impact

Abstract Introduction: Multiple Myeloma (MM) is an incurable disease. In young patients, autologous bone marrow transplantation (ABMT) remains a cornerstone treatment after induction therapy. Induction therapy has varied during time, from alkylating polychemotherapy (VBAD,VCMP) or VAD chemotherapy (AVAD) to Velcade-Dexametasone based regimens (VD). We present results of follow-up of a large cohort of patients treated with ABMT. We described overall survival (OS; from transplant to death by any cause) and progression free survival (PFS; from transplant to death by any case or progressive disease defined by reappearance by inmunofixation, or duplication of monoclonal peak after ABMT) , and the impact of induction therapy regiments. Patients: 183 patients transplanted from 2002 to 2017. The median age of the patients was 59 years (33-72). Before 2008 all the patients were treated in alkylating based chemotherapy (42 patients). After 2008 patients were treated with VD based regimens (141patients). Only 12 patients received maintenance therapy based in PETHEMA trials 2005 and 2012. No one patient received a planed second transplant; only 32 patients received a second transplant after relapse as consolidation therapy. Results: Median follow-up of patients still alive is 3.65 years (0.15-14.77). Median OS of all patients was 9.12 years (95% confidence interval (CI): 6.28-NR); Median PFS was 3.02 years(95% CI: 2.46-3.76). At 13 years only 2% of patients remains progression free (CI: 0.00-17%). There were significant differences between patients treated before and after VD regimens. The median OS of patients treated with APVAD was significantly shorter compared to VD (6.22 years, CI[3.39-12] vs. NR, CI[6.28-NR], p=0.025) (HR=0.49, p=0.01). Conclusions: VD schemes of induction before ABMT have improved remarkably OS inpatients with Myeloma; nonetheless, plateau is not observed in EFS. Further analysis must address if EFS could represent a strong indicator of OS, mainly due to novel effective salvage therapies after relapse/refractoriness could be a confounding factor. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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