Publications (9) View all
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Article: hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia: associations with immunophenotype and cytogenetic subgroup.
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ABSTRACT: Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase (hTERT) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51-61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres (p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups.Experimental hematology 09/2011; 39(12):1144-51. · 3.11 Impact Factor -
Article: Fish oil delays lymphoma progression in the TLL mouse.
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ABSTRACT: The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1-year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function.Leukemia & lymphoma 10/2010; 51(11):2092-7. · 2.40 Impact Factor -
Article: Vascular density in childhood acute lymphoblastic leukaemia correlates to biological factors and outcome.
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ABSTRACT: The issue of angiogenesis and its clinical relevance in childhood acute lymphoblastic leukaemia (ALL) is controversial. In the present study, microvessel density (MVD), analysed in 185 diagnostic bone marrow biopsies, was higher in T-cell ALL compared to B-cell precursor (BCP)-ALL (P = 0.013). In the BCP group, cases with t(12;21) were characterized by a low MVD while patients with high-hyperdiploid leukaemia (HeH, 51-61 chromosomes) showed a high MVD compared to other BCP patients (P = 0.001 and 0.002 respectively). There was a correlation between MVD and white blood cell (WBC) count in high-risk BCP patients (P = 0.021). In addition, BCP patients with a high marrow reticulin fibre density and high MVD had an unfavourable outcome compared to the other BCP patients (P = 0.002). The fraction of vessels in which lumina were filled with blasts (blast congested vessel fraction) correlated strongly with WBC count (P < 0.001). These findings indicate that the angiogenic process interacts with other stroma-factors, such as reticulin fibre density, in its effect on outcome, and is coupled to both the ALL genotype and phenotype. One possible implication is that different subtypes of childhood ALL may respond differently to anti-angiogenic drugs as a supplement in first-line treatment.British Journal of Haematology 07/2009; 146(5):521-30. · 4.94 Impact Factor -
Article: Exit of pediatric pre-B acute lymphoblastic leukaemia cells from the bone marrow to the peripheral blood is not associated with cell maturation or alterations in gene expression.
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ABSTRACT: Childhood pre-B acute lymphoblastic leukemia (ALL) is a bone marrow (BM) derived disease, which often disseminates out of the BM cavity, where malignant cells to a variable degree can be found circulating in the peripheral blood (PB). Normal pre-B cells are absolutely dependent on BM stroma for survival and differentiation. It is not known whether transformed pre-B ALL cells retain any of this dependence, which possibly could impact on drug sensitivity or MRD measurements. Pre-B ALL cells, highly purified by a novel method using surface expression of CD19 and immunoglobulin light chains, from BM and PB show a very high degree of similarity in gene expression patterns, with differential expression of vascular endothelial growth factor (VEGF) as a notable exception. In addition, the cell sorting procedure revealed that in 2 out of five investigated patients, a significant fraction of the malignant cells had matured beyond the pre-B cell stage. The transition of ALL cells from the BM into the circulation does not demand, or result in, major changes of gene expression pattern. This might indicate an independence of BM stroma on the part of transformed pre-B cells, which contrasts with that of their normal counterparts.Molecular Cancer 02/2008; 7:67. · 3.99 Impact Factor -
Article: Antitumor activity of the angiogenesis inhibitor TNP-470 on murine lymphoma/leukemia cells in vivo and in vitro.
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ABSTRACT: The aim of this study was to evaluate the effects of an angiogenesis inhibitor in a non-immunocompromised setting in which transplanted tumor cells home and expand in a manner mimicking the original tumor in the donor. We used a novel animal model for T-cell lymphoma/leukemia (TLL) to test the antitumor effect of TNP-470, a well-established angiogenesis inhibitor. Cells from spontaneously arisen TLL tumors were transferred to syngenic recipients. The mice were treated with TNP-470 (30 mg/kg) or vehicle every other day for 2 weeks. Mice were sacrificed on day 15 after transfer, and body and organ weights were measured. Cell cycle and morphologic analysis was performed on cells and/or sections from selected organs. The cytotoxic effect of TNP-470 was assayed in vitro using the TLL-M and HL-60 cell lines. TNP-470 treatment significantly reduced total tumor load and tumor mass in specific organs infiltrated with lymphoma/leukemia. This was associated with an increased apoptosis in these organs. We also observed side effects of TNP-470 not previously reported, such as diminished extramedullary erythropoiesis and disrupted liver morphology. In vitro TLL-M cells were resistant to cytotoxic effects of moderate doses of TNP-470. TNP-470 treatment has a beneficial effect on tumor load in the TLL transfer model, most likely caused by the antiangiogenic effect of TNP-470. This is supported by the observation of increased apoptosis in infiltrated organs. The TLL transfer model is well suited for further studies of combinations with TNP-470 or other angiogenesis inhibitors and cytotoxic drugs.Experimental Hematology 03/2003; 31(2):143-9. · 2.90 Impact Factor
