Prognostic factors in hodgkin lymphoma

Hodgkin lymphoma (HL) is among the neoplastic diseases that has the best long-term outcome after cytotoxic treatment. Cure rates approach 80-90%; however, 15-20% of patients will be resistant to therapy (primary refractory) or relapse after treatment. Prognostic factors should help to stratify treatment according to the risk profile and identify patients at risk for failure. Significance of prognostic factors partly depends on the efficacy of the treatments administered, since new effective therapies can variably counterbalance the adverse effects of some unfavorable clinical determinants. As a consequence, some prognostic factors thought to be important in the past may become meaningless when modern successful therapies are used. Therefore, the value of prognostic factors has to be updated periodically, and then adapted to new emerging biomarkers. Besides the prognostic role of PET imaging, tissue and circulating biomarkers, as the number of tumor-infiltrating macrophages, cytokine and chemokine levels and profiling of circulating nucleic acids (DNA and microRNAs) have shown promise

Iron in Hodgkin's lymphoma

Anemia is a frequent finding of Hodgkin's lymphoma (HL) diagnosis. It is usually mild, with hemoglobin levels between 10 and 12 g/dl; it is rarely (<10% of cases) a result of bone marrow infiltration; and it displays the characteristics of the anemia of chronic disease due to abnormalities in iron metabolism. The inflammatory cytokine IL-6 is frequently up-regulated in Hodgkin's lymphoma, and IL-6 levels are strongly associated with hepcidin, the main regulator of iron metabolism. Elevated hepcidin levels result in iron restriction and signs of anemia of chronic disease. In addition, the abundant microenvironment surrounding the neoplastic Hodgkin's and Reed-Sternberg cells may contribute to alterations in iron metabolism. Tumor-infiltrating macrophages can sequester iron using scavenger receptors. Iron-restricted anemia at HL diagnosis can be aggravated by intensive chemotherapy, and iron overload may become clinically relevant in heavily treated patients with relapsed or refractory disease undergoing high-dose chemotherapy and stem cell transplantation

Anemia in Hodgkin's lymphoma: the role of interleukin-6 and hepcidin.

Contains fulltext : 88183.pdf (publisher's version ) (Open Access)PURPOSE: Cytokines play a pivotal role in Hodgkin's lymphoma (HL). Because interleukin-6 (IL-6) induces expression of hepcidin, one of the principal regulators of iron metabolism, we studied the contribution of hepcidin in anemia in HL at diagnosis. PATIENTS AND METHODS: Plasma samples from 65 patients with HL were analyzed for hepcidin levels using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry; cytokine levels were analyzed using enzyme-linked immunosorbent assays and parameters of iron metabolism and acute-phase reaction. RESULTS: Hepcidin plasma levels were significantly higher in HL patients when compared with controls, independent of the presence of anemia (P = .001). In the subset of patients with anemia, hepcidin levels inversely correlated with hemoglobin levels (P = .01). Analyzing parameters of iron metabolism, hepcidin levels showed a positive correlation with ferritin (P 2 (P = .005). CONCLUSION: Our findings suggest that in HL, hepcidin is upregulated by IL-6. Elevated hepcidin levels result in iron restriction and signs of anemia of chronic inflammation, although hepcidin-independent mechanisms contribute to development of anemia in HL

Gene expression profiling of myelodysplastic CD34+ hematopoietic stem cells treated in vitro with decitabine.

Abnormal gene promoter methylation contributes to deregulate gene expression of hematopoietic progenitors in myelodysplastic syndromes (MDS). We analyzed the gene expression profile of myelodysplastic and normal CD34+ hematopoietic stem cells (HSCs) treated in vitro with decitabine. We identified a list of candidate tumor suppressor genes, expressed at low levels in MDS HSCs and induced by hypomethylating treatment only in MDS, but not in normal HSCs. Real-time RT-PCR confirmed reduced CD9 expression in MDS CD34+ and bone marrow mononuclear cells, compared to normal controls. CD9 was specifically up-regulated by decitabine treatment in myelodysplastic CD34+ cell

PTEN/PI3K/AKT PATHWAY DYSREGULATION IN MYELODYSPLASTIC GRANULOCYTES

Background. Patients with Myelodysplastic Syndromes are at increased risk of infections not only because of the reduced number of granulocytes, but also for their functional abnormalities. Myelodysplastic neutrophils were shown to present impaired fungicidal and bactericidal activities and reduced chemotaxis. PTEN/PI3K/AKT pathway plays a crucial role in mediating cellular response to chemotactic stimuli. Aims. To study gene expression of PTEN/PI3K/AKT signaling pathways in myelodysplastic granulocytes compared to the normal counterpart. Methods. We evaluated PTEN mRNA expression in peripheral blood granulocytes isolated by Ficoll gradient centrifugation and osmotic erythrolysis from 30 patients with MDS and 12 normal controls by Sybr Green-based realtime RT-PCR, using Abl as reference gene. Data were expressed as 2-ΔCt. DNA methylation of two regions of the PTEN promoter (from -1223 bp to -1123 bp and from -300 bp to -128 bp) was studied by Methylation-specific PCR on bisulfite-treated DNA from 19 MDS and 6 controls. The gene expression profile of 84 genes belonging to the PTEN/PI3K/AKT signaling pathway was studied on granulocytes from 10 MDS patients and 10 matched normal control using the Human PI3K-AKT Signaling Pathway RT² Profiler® PCR Arrays (SABiosciences, Qiagen). Patients’ cohort used for PCR arrays included the following MDS subtypes: 2 RCMD, 2 RAEB1, 4 RAEB2, 1 CMML and 1 t-MDS. Selected housekeeping genes were GAPDH, RPL13A and HPRT1. Data analysis was performed using the RT² Profiler® PCR Array Analysis Template v3.3. Results. PTEN mRNA was significantly down-regulated in myelodysplastic versus normal granulocytes (median 157,59 and 401,22, respectively, p=0.029). No significant differences in PTEN mRNA levels were observed in different MDS subtypes. PTEN promoter was not methylated in MDS and control granulocytes. Ten genes belonging to the PTEN/PI3K/AKT signaling pathway were found to be significantly down-regulated in MDS versus controls, including NFKBIA, FOS, AKT1, MAPK3, RBL2, RPS6KA1, GRB2, PIK3CG, RAF1 and ADAR (fold change less than -2 and p<0.05). Among studied genes, the most significantly suppressed was NFKBIA (fold change: -5,63, p=0.004) which encodes for the NFKB inhibitor-α, whose reduction might contribute to deregulated signaling across the PI3KT-AKT pathway in myelodysplastic granulocytes.Summary/ Conclusions. Deregulation of PTEN/PI3K/AKT signaling pathway can contribute to granulocytic dysfunction in MDS

Gene expression profiling of myelodysplastic CD34+ hematopoietic stem cells treated in vitro with decitabine

Abnormal gene promoter methylation contributes to deregulate gene expression of hematopoietic progenitors in myelodysplastic syndromes (MDS). We analyzed the gene expression profile of myelodysplastic and normal CD34+ hematopoietic stem cells (HSCs) treated in vitro with decitabine. We identified a list of candidate tumor suppressor genes, expressed at low levels in MDS HSCs and induced by hypomethylating treatment only in MDS, but not in normal HSCs. Real-time RT-PCR confirmed reduced CD9 expression in MDS CD34+ and bone marrow mononuclear cells, compared to normal controls. CD9 was specifically up-regulated by decitabine treatment in myelodysplastic CD34+ cells.Abnormal gene promoter methylation contributes to deregulate gene expression of hematopoietic progenitors in myelodysplastic syndromes (MDS). We analyzed the gene expression profile of myelodysplastic and normal CD34+ hematopoietic stem cells (HSCs) treated in vitro with decitabine. We identified a list of candidate tumor suppressor genes, expressed at low levels in MDS HSCs and induced by hypomethylating treatment only in MDS, but not in normal HSCs. Real-time RT-PCR confirmed reduced CD9 expression in MDS CD34+ and bone marrow mononuclear cells, compared to normal controls. CD9 was specifically up-regulated by decitabine treatment in myelodysplastic CD34+ cells

Analysis of genome-wide methylation and gene expression induced by 5-aza-2'-deoxycytidine identifies BCL2L10 as a frequent methylation target in acute myeloid leukemia.

Epigenetic changes play a role in the pathogenesis of myeloid malignancies, and hypomethylating agents have shown efficacy in these diseases. We studied the apoptotic effect, genome-wide methylation, and gene expression profiles in HL60 cells following 5-aza-20-deoxycytidine (decitabine; DAC) treatment, using microarray technologies. Decitabine treatment resulted in a decrease in global DNA methylation, corresponding to 4876 probeset IDs with significantly reduced methylation levels, while the expression of 2583 IDs was modified. The integrated analysis identified 160 genes demethylated and up-regulated by decitabine, mainly including development and differentiation pathway genes. Gene targets of Polycomb group protein regulation were overrepresented in this group. Apoptosis was induced by decitabine, and apoptosis-specific PCR arrays more precisely indicated decitabine-induced up-regulation of 13 apoptosis-related genes, in particular DAP-kinase 1 and BCL2L10. Correspondingly, in primary patient samples, BCL2L10 was hypermethylated in 45% of AML, 43% of therapyrelated myeloid neoplasms, 12% of MDS, and in none of the controls. In conclusion, decitabine induces global demethylation and gene expression, in particular of Polycomb target genes involved in development and differentiation pathways. The apoptotic gene BCL2L10 is a frequent target for aberrant promoter methylation in patients with acute leukemia, de novo and therapy-related

Interleukin-6 plasma levels are modulated by a polymorphism in the NF-\u3baB1 gene and are associated with outcome following rituximab-combined chemotherapy in diffuse large B-cell non-Hodgkin lymphoma.

Peripheral blood cytokines are known prognostic parameters in diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy, but their role after the introduction of rituximab is unknown. Seven polymorphisms in the promoter regions of IL-6, IL-10 and NF-\u3baB1 genes were assessed in 167 patients with DLBCL and 99 controls and correlated with interleukin-6 (IL-6) and IL-10 plasma levels. Outcome was analyzed in 137 patients treated with rituximab-based chemotherapy. The NF-\u3baB1 - 94ATTG deletion was associated with increased IL-6 and IL-10 in DLBCL. High IL-6 concentration correlated with unfavorable prognostic factors included in the international prognostic index (IPI) and predicted for inferior progression-free (p = 0.007) and overall survival (p = 0.02). IL-6 levels remained a significant outcome predictor also including IPI as a covariate (p = 0.006 for progression-free survival). Our data suggest that the NF-\u3baB1 genetic background influences IL-6 production in DLBCL, and that high IL-6 concentration is an independent prognostic factor also in the "rituximab era.