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  • 1
    Electronic Resource
    Electronic Resource
    Soluble factor(s) released by the PF-382 T-cell line enhances the stimulatory effect of monocytes on the BFU-E growth (1988)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 135 (1988), S. 127-132 
    Details
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: PF-382 is a human T-cell line that has been shown to elaborate factors that modulate normal hemopoiesis in vitro. In the present study we report that this cell line constitutively releases in both serum-containing and serum-free supernatants a potent enhancer of BFU-E growth. The factor(s), partially purified by gel filtration, is a heat-stable molecule(s) degradable by trypsin and 2-mercaptoethanol treatments, equally active on bone marrow and peripheral blood erythroid progenitor cells, but not on CFU-GM. Unlike other sources of BPA, this stimulatory factor(s) exerts its effect in the presence of mononuclear adherent cells. In fact, the addition of conditioned medium obtained by 48 hr preincubation of isolated monocytes with 10% PF-382 supernatant (M-CM2) or the concomitant addition of supernatant from PF-382 cells (PF-382-CM) and from unstimulated monocytes (M-CM1) are capable of fully replacing the presence of monocytes in the BFU-E assay. Since the independent addition of PF-382-CM or of M-CM1 is devoid of stimulatory function, we suggest that the PF-382 derived BFU-E growth inducer, which differs from IL-1, IL-3, IL-4, GM and G-CSF, exerts its activity “via” a synergistic mechanism with a monokine.
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    URL: http://dx.doi.org/10.1002/jcp.1041350118
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  • 2
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    Incidence of Cytogenetic Abnormalities in Newly Diagnosed Binet Stage A B-CLL and Relationship with Prognostic Biomarkers: Preliminary Results On 305 Patients Included in the Prospective O-CLL1 GISL Study. (2009)
    American Society of Hematology
    Details
    Publication Date: 2009-11-20
    Description: Abstract 2341 Poster Board II-318 Background. The clinical heterogeneity of chronic lymphocytic leukemia (CLL) requires parameters to stratify patients into prognostic subgroups to adapt treatment ranging from ‘watch and wait’ to allogeneic stem cell transplantation. To this end, several parameters such as lymphocyte doubling time, β-2 microglobulin, CD38 and ZAP-70 expression, immunoglobulin variable heavy chain (IgVH) mutation status and genetic abnormalities, as assessed by fluorescence in situ hybridization (FISH), have been integrated in clinical practice. Aims. In the present study, we investigated by FISH the incidence of the known major cytogenetic alterations (+12 and 13q14, 17p13, 11q23 deletions) in a series of Binet A B-CLL patients included in the prospective O-CLL1 GISL study started in April 2007. Methods. Molecular markers characterization and FISH analyses were performed as previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). A cut-off value of 2% was used to distinguish mutated and unmutated patients. CD38 and ZAP-70 were determined by flow-cytometry and a 30% cut-off was used to distinguish between positive or negative cases. Results. Up to date, 326 patients have been enrolled in the trial and FISH data concerning trisomy 12 and 13q14, 17p13, 11q23 deletions were available in 305 patients. At least one abnormality was found in 197 (64%) cases. The most frequent was del(13)(q14) (150/305, 49%), followed by +12 (40/303, 13%) (in one and three cases accompanied by 17p13 and 13q14 deletions, respectively), del(17)(p13) (7/305, 2%) and del(11)(q23) (17/305, 5%). 13q14 deletion was found as a sole abnormality in 134 patients; in the remaining cases, it was combined with +12 (3 pts) and 17p13 (3 pts) or 11q23 (10 pts) deletions. Among patients with 13q14 deletions, 99 were monoallelic, 12 biallelic and 39 showed a combination of the two patterns. Biomarkers data were available in all of the patients: 95/305 (31%) cases had unmutated IgVH genes; ZAP-70 and CD38 were positive in 117/305 (38%) and 72/305 (23%) cases, respectively. Concerning the distribution of cytogenetic aberrations, the unmutated IgVH group included 29/150 (19%) 13q14 deleted cases, 23/40 (57%) cases with trisomy 12 and 4/7 (57%) and 16/17 (94%) with 17p13 and 11q23 deletions, respectively. ZAP-70-positive groups included 43/150 (28%) 13q14 deleted cases, 26/40 (65%) cases showing trisomy 12 and 5/7 (71%) and 12/17 (70%) with 17p13 and 11q23 deletions, respectively. Finally, CD38-positive cases included 18/150 (12%) 13q14 deleted cases, 26/40 (65%) cases carrying trisomy 12 and 5/7 (71%) and 7/17 (41%) with 17p13 and 11q23 deletions, respectively. The percentages of IgVH mutations significantly correlated with cytogenetic alterations; namely, 5.8±0.3 for cases with del(13)(q14), 4.6±0.4 for normal karyotype, 2.6±0.5 in +12, 0.3±0.2 in del(11)(q23), and 1.7±0.9 in del(17)(p13) cases (p for trend
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  • 3
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    Molecular and Functional Effects of the Novel MEK Inhibitor PD0325901 in Preclinical Models of Human Leukemias. (2006)
    American Society of Hematology
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    Publication Date: 2006-11-16
    Description: The Raf/MEK/ERK signaling module plays a pivotal role in the regulation of cell proliferation, survival, and differentiation. Our group, among others, has recently demonstrated that this pathway is frequently dysregulated in hematological malignancies and may constitute an attractive therapeutic target, particularly in AML. Here we investigated the effects of PD0325901, a novel MEK inhibitor, on phospho-protein expression, gene expression profiles, cell proliferation, and apoptosis in cell line models of AML, ALL, multiple myeloma (MM), ex vivo-cultured primary AML blasts, and oncogene-transformed hematopoietic cells. AML cell lines (OCI-AML2, OCI-AML3, HL-60) were strikingly sensitive to PD0325901 (IC50: 5–19 nM), NB4 (APL) and U266 (MM) showed intermediate sensitivity (IC50: 822 and 724 nM), while all the lymphoid cell lines tested and the myeloid cell lines U937 and KG1 were resistant (IC50 〉 1000 nM). Cell growth inhibition was due to inhibition of cell cycle progression and induction of apoptosis. A statistically significant reduction in the proportion of S-phase cells (p=0.01) and increase in the percentage of apoptotic cells (p=0.019) was also observed in 18 primary AML samples in response to 100 nM PD0325901. Analysis of the correlation between sensitivity/resistance to PD0325901 and Ras/Raf mutation status is currently ongoing. PD0325901 effects were also examined in a panel of IL-3-dependent murine myeloid FDC-P1 cell lines transformed to grow in response to 11 different oncogenes in the absence of IL-3. Fms-, Ras-, Raf-1-, B-Raf-, MEK1-, IGF-1R-, and STAT5a-transformed FDC-P1 cells were very sensitive to PD0325901 (IC50: ~ 1 nM), while A-Raf-, BCR-ABL-, EGFR- or Src-transformed cells were 10 to 100 fold less sensitive (IC50: 10 to 100 nM); the parental, IL-3 dependent FDC-P1 cell line had an IC50 〉 1000 nM. Analysis of the phosphorylation levels of 18 different target proteins after treatment with 10 nM PD0325901 showed a 5- to 8-fold reduction in ERK-1/2, observed only in sensitive cell lines, and a 2-fold reduction in JNK and STAT3 phosphorylation. PD0325901 (10 nM) treatment also profoundly altered the gene expression profile of the sensitive cell line OCI-AML3: 96 genes were modulated after 24 h (37 up- and 59 down-regulated), most of which involved in cell cycle regulation. Changes in cyclin D1 and D3, cyclin E, and cdc 25A were also validated at the protein level. Overall, PD0325901 shows potent growth-inhibitory and pro-apoptotic activity, indicating that MEK may be an appropriate therapeutic target in an array of different hematological malignancies. Further preclinical/clinical development of this compound is warranted, particularly in myeloid leukemias.
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  • 4
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    Chronic Lymphocytic Leukemia (CLL) with Discordance in ZAP-70 Expression and IgVH Mutation Status. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: In CLL patients, ZAP-70 expression is associated with an unmutated status of the variable immunoglobulin heavy chain gene (IgVH) region. Both features bear an adverse prognostic value. However, in various published series there is a proportion of cases with discordance in the expression of these two markers (i.e. ZAP-70-/IgVH unmutated or ZAP-70+/IgVH mutated) ranging from 5 to 30%. In order to clarify the outcome of this subgroup of patients, information on the clinico-biological features of the discordant cases is becoming increasingly more relevant. From November 2002 to April 2006, we evaluated ZAP-70 and CD38 expression, IgVH mutation status and cytogenetic aberrations by FISH in 125 young and untreated patients: 69 males, 56 females, with a median age of 51 years (range 29–64). According to Binet’s staging system, 81% were stage A, 15% stage B and 4% stage C. Eighty % of patients presented stable disease and 20% progressive disease. After a median follow-up of 40 months (range 3–191) from diagnosis, 32% of cases have required therapy. ZAP-70, evaluated by immunocytochemistry and flow-cytometry, was positive (≥7%) in 36% of cases, IgVH genes were unmutated (≥98% homology) in 25% and CD38 was positive (≥7%) in 18%. The correlations between ZAP-70/IgVH, CD38/IgVH and CD38/ZAP-70 were highly significant (p≤0.001 each) with a proportion of discordant cases of 21%, 16% and 24%, respectively. Focusing on 114 cases with available data for both ZAP-70 and IgVH mutation status, three groups were identified: 23 ZAP-70+/IgVH unmutated, 67 ZAP-70-/IgVH mutated, 24 discordant cases. Significant differences were found in terms of distribution of cytogenetic aberrations, CD38 expression and atypical lymphocyte morphology (Table I). Only 2 cases showed V3-21 usage: both were IgVH mutated, 1 was ZAP-70+ and the other ZAP-70-. Of the 24 discordant cases, 18 (75%) were ZAP-70+/IgVH mutated and 6 (25%) ZAP-70-/IgVH unmutated. No significant difference was shown between the two groups regarding the presence of poor risk genetic abnormalities del(17p), del(11q) and +12 (p=0.17), CD38 expression (p=0.2), atypical lymphocyte morphology (p=0.12). Although the follow-up is still short, ZAP-70 and IgVH status significantly predicted treatment-free interval (TFI), individually (p
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  • 5
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    Transfer of the Interleukin-2 Gene Into Human Cancer Cells Induces Specific Antitumor Recognition and Restores the Expression of CD3/T-Cell Receptor Associated Signal Transduction Molecules (1997)
    American Society of Hematology
    Details
    Publication Date: 1997-01-01
    Description: Normal peripheral blood mononuclear cells (PBMC) were cocultured with a human lung cancer cell line (LC89) transduced with the interleukin-2 (IL-2), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and tumor necrosis factor-α (TNF-α) genes to evaluate the capacity of the engineered cells to: allow survival of CD3+ and CD56+ cells, generate cytotoxic effectors with HLA class I restricted and unrestricted antitumor activity, and interfere in the molecular organization of the CD3/T-cell receptor associated signal transduction machinery. When PBMC were cultured up to 3 weeks with IL-2 releasing LC89 cells (LC89/IL-2), the number of viable CD3+ and CD56+ lymphocytes was much greater than in cultures with parental cells or with LC89 cells transduced with the other cytokine genes. After 1 week of coculture, a variable degree of restricted and unrestricted killing directed against different targets was observed. When the cultures were prolonged up to 3 weeks, LC89/IL-2 cells induced a marked increase in specific cytotoxic activity, which was coupled to a further enhancement of unrestricted lytic function. In the presence of LC89/IL-7 cells the degree of specific lysis remained unchanged, whereas unrestricted effectors were markedly decreased. No cytotoxic activity could be induced by LC89/GM-CSF and LC89/TNF-α cells in the few lymphocytes surviving after 3 weeks of culture. Coculture of parental LC89 cells with PBMC was consistently associated with a downmodulation in the expression of the CD3 ζ chain, as well as of the tyrosine kinases p56lck and ZAP-70. On the contrary, LC89/IL-2 cells, and not LC89 cells transduced with the IL-7, GM-CSF, or TNF-α gene, were capable of reverting the immunosuppressive effect exerted by the tumor cells. This protective effect could be maintained in cultures prolonged up to 4 weeks. When the same cultures were set up in Transwell, ie, with a membrane separation between cancer cells and PBMC, the expression of the CD3 ζ chain and of the p56lck and ZAP-70 tyrosine kinases remained unchanged under all culture conditions, indicating that the downmodulation of T-cell signal transduction molecules requires a direct cell to cell contact. These results show that transfer of the IL-2 gene into the DNA of human cancer cells promotes both restricted and unrestricted antitumor activity, and is capable of restoring and maintaining the expression of molecules involved in the process of T-cell mediated tumor cell recognition, thus underlining the potential role of the IL-2 gene in the design of vaccination protocols with cytokine gene transduced cancer cells.
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  • 6
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    Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia (ALL): An Update of the GIMEMA Experience. (2009)
    American Society of Hematology
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    Publication Date: 2009-11-20
    Description: Abstract 3097 Poster Board III-34 Backgound Adolescent and young (
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  • 7
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    A New Method To Evaluate the Prognostic Value of Response to Prednisone Pre-Treatment in Adult (15–60 Yrs) Patients with Acute Lymphoblastic Leukemia: Results of the GIMEMA LAL 2000 Study. (2005)
    American Society of Hematology
    Details
    Publication Date: 2005-11-16
    Description: The prognostic significance of the response to initial prednisone treatment in adult ALL has been recently emphasized. Prednisone response is usually defined on the basis of the peripheral leukemic blast count. The threshold value for the defintion as good or poor prednisone response is 1000 blasts/mmc on day 8 of prednisone pre-treatment. The drawback of this definition is the difficulty of classifying patients with less than 1000 blasts at diagnosis. In the LAL2000 GIMEMA study we therefore evaluated whether the blast reduction rate, which is not affected by the initial blast level, could be a factor with comparable prognostic value. The protocol design provided a 7-day (−6 to 0) pre-treatment phase with an escalating dose of prednisone up to 60 mg/sqm. On day 1 before starting the induction the response was assessed both according to the absolute blast count (〈 versus ≥ 1000/mmc) (criterion 1) and according to the blast reduction rate ≥ 75% (criterion 2) in the peripheral blood. The induction included high dose Daunorubicin; for patients in complete remission (CR) this was followed by consolidation with high dose ARA-C, chemo and radio prophylaxis of the central nervous system, and periodical reinduction over a three years maintenance period. Patients with adverse cytogenetic features [i.e. t(9;22), t(4;11), t(1;19)] who achieved a CR were treated according to the HAM protocol that included high dose ARA-C and Mitoxantrone followed by Imatinib for Ph+ ALL and by allogeneic or autologous hemopoietic stem cells transplantation for the others. Between September 2000 and December 2003 a total of 368 patients were evaluable for response to induction. The median age was 35 years (15–60) and median WBC count 15′109/L (0.3–872); 72 (20%) were T ALL and 121 (33%) had cytogenetic high risk features (104 (86%) Ph+, 4 (3%) t(4;11) and 13 (11%) t(1;19)). Eighty-seven percent of the patients were evaluable for response to steroid pre-treatment: ’responders’ were 75% according to criterion 1 (blast
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  • 8
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    Dasatinib as Front-Line Monotherapy for the Induction Treatment of Adult and Elderly Ph+ Acute Lymphoblastic Leukemia (ALL) Patients: Interim Analysis of the GIMEMA Prospective Study LAL1205. (2007)
    American Society of Hematology
    Details
    Publication Date: 2007-11-16
    Description: Dasatinib (SPRYCEL, formerly BMS-354825) is a potent, orally active inhibitor of the BCR-ABL, c-KIT and SRC family of kinases, which play a critical role in oncogenesis and persistence of malignant phenotypes. In preclinical studies, dasatinib has proven to be a more potent inhibitor of BCR-ABL and c-KIT than imatinib mesylate, and has been shown to be effective in the clinical setting in patients with all phases of chronic myeloid leukemia (CML) or Ph+ ALL resistant to or intolerant of imatinib. We present the first interim results of the GIMEMA protocol LAL 1205 designed to assess the efficacy, safety and tolerability of dasatinib in Ph+ ALL patients at the onset of the disease. The protocol enrolls patients ≥18 years who receive dasatinib p.o. at a dose of 70 mg BID. A steroid regimen (prednisone up to 60mg/m2 day po) is started 7 days prior to the first dasatinib administration and is continued until day 31. The 7-day prednisone pre-phase allows identification of the BCR/ABL transcript. Dasatinib is administered for a total of 84 days. Two intrathecal methotrexate infusions at days +22 and +43 are included. All cases are processed and analyzed through central handling of samples at presentation and are investigated for morphology, immunophenotype, cytogenetics and molecular biology. Minimal residual disease (MRD) is also centrally evaluated by flow-cytometry and Q-RT-PCR at days +22, +43, +57 and +84. A total of 23 patients with BCR/ABL+ ALL have been enrolled to date; median age 57 yrs (30–74), 15 females. All 23 patients have shown a complete hematological response by day +22. One patient relapsed after completing dasatinib administration and died of disease progression, while all other patients are at present alive and well after a median time of observation from diagnosis of 4.5 months (1.7 – 8.0). Monitoring of MRD documented that dasatinib plus prednisone was capable of inducing a very marked clearance of leukemic cells already at day +22, confirmed and strengthened in the subsequent steps of observation. The results of the immunophenotypic and BCR/ABL Q-RT-PCR monitoring are reported in the accompanying table: This interim analysis indicates that in adult and elderly Ph+ ALL induction monotherapy with dasatinib plus prednisone is capable of inducing a rapid hematological remission in all patients so far treated without important toxicity and no fatality. This is associated with a very marked and rapid debulking of the disease as documented by the close phenotypic and molecular monitoring of MRD. DAYS IMMUNOPHENOTYPE Q-RT-PCR (% of leukemic cells) (copy number) 1% 0.01% 1 x 10²
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  • 9
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    Protein Expression of p15 and p21 Plays an Unfavorable Prognostic Role in Adult Acute Lymphoblastic Leukemia (ALL) Patients Independently of Their Gene Promoter Methylation Status. (2007)
    American Society of Hematology
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    Publication Date: 2007-11-16
    Description: Epigenetic silencing of tumor suppressor (TS) genes is a hallmark in human leukemias, particularly through DNA methylation. Cyclin-dependent kinase inhibitors (CKI) are, among other genes, frequently found methylated in their promoter region. This epigenetic modification has been described also in acute lymphoblastic leukemia (ALL). However, the relationship between aberrant DNA methylation and protein expression of TS genes has not yet been extensively evaluated in adult ALL series. The aim of this study was to analyze in primary cells from newly diagnosed adult ALL patients, uniformly treated according to the LAL2000 GIMEMA protocol, the promoter methylation status of p73, p21, p15 and p16, evaluating in addition the p21, p15 and p16 protein expression. The DNA methylation status of promoter regions was investigated, according to cell availability, using a widely accepted method based on bisulfite modification of DNA, followed by methylation-specific PCR assay (MSP). Protein expression was evaluated by Western blot. Normal peripheral blood lymphocytes, as already described, resulted unmethylated for p73, p21, p15 and p16, and did not express the p21, p15 and p16 proteins. In ALL patients, in contrast, only the p21 promoter region was found constantly unmethylated. The p15, p16 and p73 promoter genes were found methylated in 15/37 (40.5%), 8/43 (18.6%) and 9/36 (25%) patients, respectively. Only 2/23 cases (8.6%) resulted simultaneously methylated for p15, p16 and p73. The p21 and p15 protein expression was found in 28/85 (32.9%) and 44/85 cases (51.8%), respectively. The p16 protein, in contrast, was never expressed. The p16 methylation was associated with the T-ALL (P=0.005) phenotype and with higher white blood cell (WBC) counts (P=0.027). Resistance to spontaneous induction of apoptosis was significantly associated with p21 protein expression (P=0.019) and its co-expression with p15 (P=0.049). Achievement of CR was not influenced by gene methylation status, nor by single protein expression. Interestingly, the co-expression of p15 and p21 was associated with failure to induction treatment: only 6/63 (9.5%) patients co-expressing p15 and p21 obtained a CR (P=0.027). Multivariate analysis confirmed the unfavorable role of this protein co-expression (P=0.059) on CR achievement. In contrast, once patients achieved remission, p21 protein expression was associated with a prolonged DFS, as confirmed by multivariate analysis for DFS (P=0.039). In conclusion, p15 and p21 protein expression plays an unfavorable prognostic role in adult ALL patients independently of the p73, p21, p15 and p16 gene promoter methylation status.
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  • 10
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    Transfer of the Interleukin-2 Gene Into Human Cancer Cells Induces Specific Antitumor Recognition and Restores the Expression of CD3/T-Cell Receptor Associated Signal Transduction Molecules (1997)
    American Society of Hematology
    Details
    Publication Date: 1997-01-01
    Description: Normal peripheral blood mononuclear cells (PBMC) were cocultured with a human lung cancer cell line (LC89) transduced with the interleukin-2 (IL-2), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and tumor necrosis factor-α (TNF-α) genes to evaluate the capacity of the engineered cells to: allow survival of CD3+ and CD56+ cells, generate cytotoxic effectors with HLA class I restricted and unrestricted antitumor activity, and interfere in the molecular organization of the CD3/T-cell receptor associated signal transduction machinery. When PBMC were cultured up to 3 weeks with IL-2 releasing LC89 cells (LC89/IL-2), the number of viable CD3+ and CD56+ lymphocytes was much greater than in cultures with parental cells or with LC89 cells transduced with the other cytokine genes. After 1 week of coculture, a variable degree of restricted and unrestricted killing directed against different targets was observed. When the cultures were prolonged up to 3 weeks, LC89/IL-2 cells induced a marked increase in specific cytotoxic activity, which was coupled to a further enhancement of unrestricted lytic function. In the presence of LC89/IL-7 cells the degree of specific lysis remained unchanged, whereas unrestricted effectors were markedly decreased. No cytotoxic activity could be induced by LC89/GM-CSF and LC89/TNF-α cells in the few lymphocytes surviving after 3 weeks of culture. Coculture of parental LC89 cells with PBMC was consistently associated with a downmodulation in the expression of the CD3 ζ chain, as well as of the tyrosine kinases p56lck and ZAP-70. On the contrary, LC89/IL-2 cells, and not LC89 cells transduced with the IL-7, GM-CSF, or TNF-α gene, were capable of reverting the immunosuppressive effect exerted by the tumor cells. This protective effect could be maintained in cultures prolonged up to 4 weeks. When the same cultures were set up in Transwell, ie, with a membrane separation between cancer cells and PBMC, the expression of the CD3 ζ chain and of the p56lck and ZAP-70 tyrosine kinases remained unchanged under all culture conditions, indicating that the downmodulation of T-cell signal transduction molecules requires a direct cell to cell contact. These results show that transfer of the IL-2 gene into the DNA of human cancer cells promotes both restricted and unrestricted antitumor activity, and is capable of restoring and maintaining the expression of molecules involved in the process of T-cell mediated tumor cell recognition, thus underlining the potential role of the IL-2 gene in the design of vaccination protocols with cytokine gene transduced cancer cells.
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