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Cross, AH, RM Goorha, R. Nuss, FG Behm, SB Murphy, DK Kalwinsky, S. Raimondi, GR Kitchingman i J. Jr Mirro. "Acute myeloid leukemia with T-lymphoid features: a distinct biologic and clinical entity". Blood 72, nr 2 (1.08.1988): 579–87. http://dx.doi.org/10.1182/blood.v72.2.579.579.
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Abstract We studied the clinical and biologic features of 10 cases of acute leukemia that met standard French-American-British (FAB) criteria for acute myeloid leukemia (AML) but in which the blast cells also expressed the T-cell-associated CD2 surface antigen. All cases had greater than 3% myeloperoxidase and Sudan black B-positive leukemic blasts, and blasts from seven cases contained Auer rods. Reactivity of the cells with a panel of monoclonal antibodies (MAbs) indicated that leukemic cells in all cases expressed myeloid-associated (CD11b, CD13) surface antigens, further supporting the diagnosis of AML. However, blasts from every patient coexpressed the T-cell-associated surface CD2 and CD7 as well as cytoplasmic CD3 antigens. Blasts from five patients expressed surface CD25, whereas blasts from only one expressed surface CD3. Five patients had rearranged T-cell receptor beta-chain genes, whereas only three had rearranged T-cell receptor gamma-chain genes. This pattern of lineage-related gene expression appears to define a distinct subtype of AML with T-lymphoid features (CD2+ AML) and could reflect either aberrant gene expression in leukemic blasts or transformation of a pluripotent stem cell having a flexible pattern of gene expression. Clinically, these 10 patients presented at an older age with a higher leukocyte count and a higher frequency of lymphadenopathy than did children whose blast cells were characteristic of myeloid leukemia. Patients with CD2+ AML also had poorer responses to remission induction therapy (50% v 80% entered complete remission, P = .05). However, each of the five children who failed induction chemotherapy on AML protocols had a striking response to drug combinations usually reserved for lymphoid leukemia. We conclude that this leukemia with mixed lymphoid and myeloid characteristics is a distinct biologic and clinical entity.
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Cross, AH, RM Goorha, R. Nuss, FG Behm, SB Murphy, DK Kalwinsky, S. Raimondi, GR Kitchingman i J. Jr Mirro. "Acute myeloid leukemia with T-lymphoid features: a distinct biologic and clinical entity". Blood 72, nr 2 (1.08.1988): 579–87. http://dx.doi.org/10.1182/blood.v72.2.579.bloodjournal722579.
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We studied the clinical and biologic features of 10 cases of acute leukemia that met standard French-American-British (FAB) criteria for acute myeloid leukemia (AML) but in which the blast cells also expressed the T-cell-associated CD2 surface antigen. All cases had greater than 3% myeloperoxidase and Sudan black B-positive leukemic blasts, and blasts from seven cases contained Auer rods. Reactivity of the cells with a panel of monoclonal antibodies (MAbs) indicated that leukemic cells in all cases expressed myeloid-associated (CD11b, CD13) surface antigens, further supporting the diagnosis of AML. However, blasts from every patient coexpressed the T-cell-associated surface CD2 and CD7 as well as cytoplasmic CD3 antigens. Blasts from five patients expressed surface CD25, whereas blasts from only one expressed surface CD3. Five patients had rearranged T-cell receptor beta-chain genes, whereas only three had rearranged T-cell receptor gamma-chain genes. This pattern of lineage-related gene expression appears to define a distinct subtype of AML with T-lymphoid features (CD2+ AML) and could reflect either aberrant gene expression in leukemic blasts or transformation of a pluripotent stem cell having a flexible pattern of gene expression. Clinically, these 10 patients presented at an older age with a higher leukocyte count and a higher frequency of lymphadenopathy than did children whose blast cells were characteristic of myeloid leukemia. Patients with CD2+ AML also had poorer responses to remission induction therapy (50% v 80% entered complete remission, P = .05). However, each of the five children who failed induction chemotherapy on AML protocols had a striking response to drug combinations usually reserved for lymphoid leukemia. We conclude that this leukemia with mixed lymphoid and myeloid characteristics is a distinct biologic and clinical entity.
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Isakson, P. C., D. D'Angelo, J. Schetz, L. Tardelli i E. Puré. "Anti-Ig-stimulated B lymphoblasts can be restimulated via their surface Ig." Journal of Immunology 143, nr 12 (15.12.1989): 3901–8. http://dx.doi.org/10.4049/jimmunol.143.12.3901.
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Abstract Engaging AgR (surface Ig) on B lymphocytes leads to rapid inositol phosphate turnover and elevation of intracellular [Ca2+]. Continuous receptor occupancy (greater than 18 h) by anti-Ig leads to transit of most B lymphocytes from G0 to G1 stage of the cell cycle (blast transformation); a fraction of cells continue into S phase but do not proliferate continuously in the absence of growth factors. Prolonged exposure to ligand can induce receptor desensitization of some receptors. We therefore investigated whether such desensitization occurs in B cells activated by insolubilized anti-Ig. Resting B cells and anti-Ig-activated blasts were examined for their potential to elevate [Ca2+]i, maintain viability, and synthesize DNA in response to reexposure to anti-Ig. B cells and anti-Ig blasts had similar basal [Ca2+]i levels. Anti-Ig blasts retained the capacity to increase [Ca2+]i in response to anti-Ig; the magnitude of the increase was equal to or greater than that observed with resting B cells and occurred in more than 90% of cells. Isolated anti-Ig blasts subcultured in the presence of T cell-derived growth factors for 3 to 5 days responded to restimulation by anti-Ig with an increase in [Ca2+]i similar to that observed in freshly isolated blasts. The B cell and B lymphoblast ion channels were found to be permeable to Ca2+ but impermeable to Mn2+. Finally, blasts restimulated by anti-Ig retained viability and incorporated low levels of [3H]thymidine for 24 h. These results suggest that AgR on activated B lymphocytes can remain functionally coupled to intracellular signaling pathways and can participate in immune responses subsequent to initial activation.
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Smith, FO, BC Lampkin, C. Versteeg, DA Flowers, PA Dinndorf, JD Buckley, WG Woods, GD Hammond i ID Bernstein. "Expression of lymphoid-associated cell surface antigens by childhood acute myeloid leukemia cells lacks prognostic significance". Blood 79, nr 9 (1.05.1992): 2415–22. http://dx.doi.org/10.1182/blood.v79.9.2415.2415.
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Abstract The prognostic significance of cell surface antigens associated with lymphoid and myeloid lineage differentiation on the blasts of children with acute myeloid leukemia (AML) was evaluated. Leukemic blasts from 176 patients enrolled on Childrens Cancer Study Group Protocol 213 determined to have AML by standard morphologic and cytochemical criteria were immunophenotyped. Cell surface antigens associated with myeloid differentiation were found on blasts from 88.1% of patients (CD15, 44%; CD33, 65%; CD36, 53%; glycoprotein Ib, 9.3%). However, blasts from 30.7% of patients expressed surface antigens thought to be specific for lymphoid lineage differentiation (CD2, 9.4%; CD5, 2.7%; CD19, 34.5%; CD20, 0.8%). In addition, CD34, a glycoprotein found on immature cells of both myeloid and lymphoid lineages, was expressed on the blast cells of 48.2% of patients. With the exception of the lymphoid lineage nonspecific antigen CD4, no correlation was found between white blood cell count at diagnosis, age, and French-American- British morphology, and the expression of any of the lymphoid- or myeloid-associated cell surface antigens studied. Nor was the expression of these antigens prognostically significant with respect to response to induction therapy, death during induction, survival, event- free survival, or survival/event-free survival following remission induction. Multivariate analysis showed that CD4 expression was not an independent predictor of outcome. Thus, this prospective study suggests that expression of lymphoid-associated cell surface antigens as well as myeloid-associated antigens by childhood AML blasts lacks prognostic significance.
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Smith, FO, BC Lampkin, C. Versteeg, DA Flowers, PA Dinndorf, JD Buckley, WG Woods, GD Hammond i ID Bernstein. "Expression of lymphoid-associated cell surface antigens by childhood acute myeloid leukemia cells lacks prognostic significance". Blood 79, nr 9 (1.05.1992): 2415–22. http://dx.doi.org/10.1182/blood.v79.9.2415.bloodjournal7992415.
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The prognostic significance of cell surface antigens associated with lymphoid and myeloid lineage differentiation on the blasts of children with acute myeloid leukemia (AML) was evaluated. Leukemic blasts from 176 patients enrolled on Childrens Cancer Study Group Protocol 213 determined to have AML by standard morphologic and cytochemical criteria were immunophenotyped. Cell surface antigens associated with myeloid differentiation were found on blasts from 88.1% of patients (CD15, 44%; CD33, 65%; CD36, 53%; glycoprotein Ib, 9.3%). However, blasts from 30.7% of patients expressed surface antigens thought to be specific for lymphoid lineage differentiation (CD2, 9.4%; CD5, 2.7%; CD19, 34.5%; CD20, 0.8%). In addition, CD34, a glycoprotein found on immature cells of both myeloid and lymphoid lineages, was expressed on the blast cells of 48.2% of patients. With the exception of the lymphoid lineage nonspecific antigen CD4, no correlation was found between white blood cell count at diagnosis, age, and French-American- British morphology, and the expression of any of the lymphoid- or myeloid-associated cell surface antigens studied. Nor was the expression of these antigens prognostically significant with respect to response to induction therapy, death during induction, survival, event- free survival, or survival/event-free survival following remission induction. Multivariate analysis showed that CD4 expression was not an independent predictor of outcome. Thus, this prospective study suggests that expression of lymphoid-associated cell surface antigens as well as myeloid-associated antigens by childhood AML blasts lacks prognostic significance.
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van Luijn, Marvin M., Maaike E. Ressing, Emmanuel J. H. J. Wiertz, Adri Zevenbergen, Martine E. D. Chamuleau, Yuri Souwer, Suzanne Ostrand-Rosenberg, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht i S. Marieke van Ham. "TAP- and Proteasome-Dependent Endogenous Antigen Loading of HLA Class II in Leukemic Blasts Introduces a Promising New Target for Generating Leukemia-Specific CD4+ T Cells". Blood 112, nr 11 (16.11.2008): 5443. http://dx.doi.org/10.1182/blood.v112.11.5443.5443.
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Abstract According to the classical HLA class II antigen presentation pathway, exogenous antigens are processed in the endosomal/lysosomal pathway and associate with HLA class II after exchange with the class II-associated invariant chain peptide (CLIP). For this reason, the relative amount of CLIP presented by HLA-DR (DR) molecules (CLIP/DR amount) can be considered as an indicator for HLA class II antigen loading. Previously, we showed that Invariant Chain (Ii) down-modulation in the Kasumi-1 and THP-1 AML cell lines led to marked declines in CLIP/DR amount [Van Luijn et al., Haematologica2008; 93(s1), Abstract 0029]. In addition, the total amount of cell surface-expressed DR was reduced on Kasumi-1 blasts, in line with the need of Ii for the transport of newly synthesized HLA class II molecules into the endosomal/lysosomal pathway. Surprisingly, in THP-1 blasts, Ii down-modulation hardly affected DR expression at the cell surface. In the present study, we further explored the Ii-independent pathway of HLA class II antigen presentation in leukemic blasts. Not only in the THP-1, but also in another AML cell line, the KG-1, Ii down-modulation had no effect on DR expression levels, as determined by flow cytometry. Since DR expression does require peptide binding, Ii-independency in these AML blasts may be achieved by endogenous antigen loading in the endoplasmic reticulum (ER). To test this hypothesis, supply of endogenously derived peptides into the ER was blocked by viral proteins interfering with the function of the transporter associated with antigen processing (TAP). As expected, TAP inhibition in KG-1 blasts by the viral UL49.5 protein (which changes the conformation of TAP and mediates its degradation) resulted in a strong down-regulation (7.7-fold) of HLA class I. Strikingly, TAP inhibition also induced a clear DR− KG-1 blast population (52.3% of total; MFI=1.4) next to the original DR+ KG-1 blast population (36.5% of total; MFI=288.9), demonstrating that DR expression is partly TAP-dependent in KG-1 blasts. Upon sorting of both populations, TAP−DR− blasts had a decreased expression of intracellular Ii as compared to TAP−DR+ blasts (3.9-fold) and wild type blasts (4.7-fold). Additionally, confocal microscopy revealed that in TAP−DR+ blasts, DR localised to the cell surface, indicating that Ii is able to rescue cell surface expression of DR. Indeed, Ii down-modulation in TAP−DR+ blasts caused a 2.3-fold decline in DR expression. The observed differences in TAP, Ii and DR expression between these KG-1 variants were confirmed by Western blot analysis. Furthermore, blocking of proteasome function by the specific inhibitors MG-132 and Bortezomib also caused a marked decrease of DR expression on KG-1 blasts (MFI declined from 289.2 to respectively 76.4 and 114.5). Accompanying reduction in HLA class I levels ascertained specific proteasome inhibition. This confirmed that at least part of the antigens presented by DR on KG-1 blasts was derived from endogenous sources. Similar results were obtained with THP-1 blasts, as both TAP and proteasome inhibition clearly affected DR expression. In line with our observations that in Kasumi-1 blasts, DR expression is Ii-dependent, addition of the TAP and proteasome inhibitors to Kasumi-1 blasts did not affect cell surface expression of DR. In conclusion, our data reveal an alternative Ii-independent, but TAP- and proteasome-dependent cross-presentation pathway in different AML cell lines, which involves HLA class II loading of endogenous antigens in the ER. Therefore, this alternative pathway may serve as a potent immunomodulatory target in leukemic blasts to activate CD4+ T cells specific for a broad range of leukemia-associated antigens.
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He, Shun, Carolyn Cheney, Susan P. Whitman, Jianhua Yu, Sumithira Vasu, William Blum, Karl-Heinz Heider, Guido Marcucci i Natarajan Muthusamy. "Decitabine Or 5-Azacitidine Pre-Treatment Does Not Compromise The Novel Fc-Engineered Antibody Mab 33.1-Mediated ADCC Against Primary AML Blasts - A Rationale For Combination Therapy". Blood 122, nr 21 (15.11.2013): 3959. http://dx.doi.org/10.1182/blood.v122.21.3959.3959.
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Abstract Introduction Acute Myeloid leukemia (AML) in patients older than 60 years is a devastating diagnosis with long-term survival rates of 10%. Elderly patients have poor survival both due to chemoresistance and presence of concomitant comorbidities rendering them ineligible for induction chemotherapy. Hence novel treatment options are warranted in this patient population. Promising activity of monoclonal antibodies such as alemtuzumab and rituximab for chronic lymphocytic leukemia (CLL) and rituximab for lymphomas has raised the potential use of antibody therapies in AML. CD33 is expressed on greater than 90% of AML blast cells while absent from all non-hematopoietic tissues. Hence CD33 is a viable target for antibody-based therapeutics in AML. Here, we tested the ex vivo efficacy of the mAb 33.1, a fully human anti-CD33 antibody Fc-engineered for increased binding to Fcγ receptors on AML cell lines and primary AML blasts. The goals of this study are to evaluate 1) the efficacy of mAb33.1 on purified allogeneic and autologous natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against primary AML Blasts; 2) to evaluate efficacy of mAb 33.1 in combination with azanucleosides (i.e. decitabine, 5-azacitidine) that are currently used in AML therapy on NK cell-mediated ADCC against primary AML blasts; and 3) to correlate the levels of surface expression of CD33 on AML blasts to the mAb 33.1 mediated ADCC. Methods mAb 33.1 mediated NK cell activation was determined by NK degranulation as determined by CD107a induction, and ADCC was determined by standard 4-hour 51Cr-release assay. An AML cell line HL60 and a total of 15 AML blast samples were used as targets in this study. NK cells enriched from normal donor PBMC (for allogeneic assays) or sorted from AML blast samples (for autologous assays) were used as effector cells. Results The mAb 33.1 induced potent ADCC activity (>40%) compared to control non-Fc engineered antibody at the concentration of 10 μg/ml in the HL60 cell line. For the AML blasts, mAb 33.1 mediated significantly higher ADCC activity when compared to the control antibody (p<0.05). The relative cytotoxicity mediated by mAb 33.1 varied among different patients, ranging from 4.4% to 65.8%. Subsequent quantification of CD33 showed that there is a positive correlation between ADCC activity and the number of surface CD33 molecules on the AML blasts. Induction of CD107a expression was also observed in both allogeneic and autologous NK cells when the blasts were labeled with mAb 33.1. Pre-treatment of the NK cells and/or target blasts with decitabine or 5-azacitidine for 48hrs, did not alter the mAb 33.1 mediated ADCC activity or CD107 induction. Conclusion mAb33.1 mediated potent ADCC activity and NK activation against AML cell lines and primary AML blasts. Both autologous and allogeneic NK cell-mediated ADCC against primary blast cells from AML patients was observed. The level of NK cell-mediated ADCC was positively associated with the levels of the surface CD33 expression on target AML blasts. Pre-treatment of either AML blasts and/or NK effector cells with Decitabine or 5-azacitidine did not compromise mAb 33.1-mediated ADCC. These pre-clinical studies support further clinical development of mAb 33.1 in combination with relevant anti-AML therapies such as decitabine or 5-azacitidine in patients with CD33 expression. Disclosures: Heider: boehringer-ingelheim: Employment.
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Galski, Hanan, Masha Simanovsky, Sagi Berlinsky i Arnon Nagler. "P-Glycoprotein (Pgp) - Dependent Drug Resistance to Imatinib at CML-BC Is Exclusively Developed in Aggressive Minor Blast Subpopulation (MS) and Can Be Reversed by Pgp Modulators". Blood 112, nr 11 (16.11.2008): 721. http://dx.doi.org/10.1182/blood.v112.11.721.721.
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Abstract CML is considered as a model of multi step-developing malignancies. Although very effective in chronic phase CML, imatinib mesylate (IM) and second generation TK inhibitors treatment are usually less effective in advanced CML (accelerated and blast crisis phases) since drug-resistant clones inevitably shortly emerge. In a recent study (Simanovsky M et al, Differentiation. 2008 Apr 29 [Epub ahead of print]), we have demonstrated that at blast crisis CML (CML-BC), blood circulating blasts of the same CML clone are heterogeneous, containing a small cell-fraction (1–3%) of blasts that are significantly more aggressive than the major malignant population. Briefly, we found that these minor subsets (MS) of blasts (both from patients and human CML-BC cell lines) have a typical highly repopulating ability, increased clonogenicity, and over expression of BCR-ABL and few other cancer-related genes. To evaluate whether the MS blasts also exhibit differential drug resistance mechanisms toward IM, we compared the two blast subsets for the level of resistance to IM in relation to expression of a functional Pgp, an ABC transporter that is the product of the ABCB1 (MDR1) gene. In the current study, we found that the MDR1 gene (but not several other ABC transporter genes) is significantly (5–7 fold) upregulated in the MS blasts, relatively to the major population. Moreover, FACS and Western analyses revealed that while Pgp could not be detected on the cell surface of the major blast subsets, Pgp is exclusively highly expressed in the MS blasts. Moreover, functional Pgp assays in the MS blasts (efflux, dose-dependent competitions, and UIC2 Pgp-specific shift assays) indicated unequivocally that IM is a substrate for Pgp. While IM efficiently inhibited the proliferation of the major blasts in dose-dependent manner, the proliferation rate of the MS blasts was essentially not affected. Furthermore, the anti-proliferative effect of IM on the MS blasts could be restored by addition of the Pgp inhibitor, R-verapamil, in dose-dependent manner. While relatively long, gradual selection in culture of the major CML-BC subsets resulted in some Pgp-independent IM-resistant clones, Pgp activity levels were shortly further elevated (by 1-order magnitude) in the MS blasts. Interestingly, FACS analyses, using different monoclonal antibodies that bind specifically to different known extra cellular epitopes of Pgp, indicated differential antibodies-epitopes binding ratios after IM selection. These stoichiometric changes suggest a topological folding shift of Pgp between its moderate to high activity (proposed model, Figure 1). In conclusion, the existence of a minor “pool” of CML blasts of both greater clonogenicity and high expression and activity levels of Pgp, apparently signify clonal evolution toward both increased malignancy and lower therapeutic sensitivity. Moreover, as both IM and Dasatinb are transported by Pgp, this study suggests that their combination therapy with Pgp-modulateors might also be clinically effective in targeting this aggressive blast population. FIGURE 1: The proposed model of topological folding of Pgp in relation to activity. FIGURE 1:. The proposed model of topological folding of Pgp in relation to activity.
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Su, F., K. Aki i N. N. Biswas. "Discriminating quarry blasts from earthquakes using coda waves". Bulletin of the Seismological Society of America 81, nr 1 (1.02.1991): 162–78. http://dx.doi.org/10.1785/bssa0810010162.
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Abstract A new quarry blast-earthquake discrimination method is presented based on the analysis of seismic coda waves. Quarry blasts and local earthquakes in the area encompassing the south-central Mojave Desert and Eastern Transverse Ranges were used to test this method. We found that the coda decay rate Qc−1 is significantly higher for quarry blasts than earthquakes for lower frequencies (1.5 and 3 Hz) for lapse time up to about 30 sec. This result is attributed to the greater contribution of surface waves to quarry blasts due to the shallowness of their source depth. The difference in Qc−1, however, disappears for lapse time greater than 30 sec for the same frequency range as well as for higher frequencies (6 and 12 Hz) for lapse time greater than 20 sec. This suggests that the coda waves, at the lapse time greater than these critical values, are dominated by the same type of body waves, probably S waves, for both quarry blasts and earthquakes. The power spectrum P0(ω) obtained after the correction for attenuation was compared between earthquakes and quarry blasts at the same stations, and a significant difference was found in the spectral shape between these two data sets. The curves of power spectrum P0(ω) versus frequency for quarry blasts decrease more sharply than for earthquakes at high frequencies, indicating a lack of energy in high frequencies for quarry blasts as compared to earthquakes. The different frequency dependence of power spectrum P0(ω) between quarry blasts and earthquakes is attributed to their different source properties and can be used for seismic discrimination of quarry blasts from earthquakes.
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Mirro, J., TF Zipf, CH Pui, G. Kitchingman, D. Williams, S. Melvin, SB Murphy i S. Stass. "Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance". Blood 66, nr 5 (1.11.1985): 1115–23. http://dx.doi.org/10.1182/blood.v66.5.1115.1115.
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Abstract The frequency and clinical significance of acute leukemia displaying both lymphoid and myeloid characteristics was determined in 123 consecutive children using a panel of lineage-associated markers. The leukemic blasts from 18 of 95 children (19%) with the diagnosis of acute lymphoblastic leukemia (ALL) by standard diagnostic criteria expressed myeloid-associated cell surface antigens. Despite immunological evidence of lymphoid differentiation (17 CALLA + and one T cell-associated antigen +) and findings of immunoglobulin gene rearrangement, blasts from these patients reacted with one to five monoclonal antibodies identifying myeloid-associated cell surface antigens (My-1, MCS.2, Mo1, SJ-D1, or 5F1). Dual staining with microsphere-conjugated antibodies and analysis by flow cytometry confirmed that some blasts were simultaneously expressing lymphoid- and myeloid-associated antigens. Conversely, blasts from seven of 28 patients (25%) with acute nonlymphocytic leukemia (ANLL), diagnosed by otherwise standard morphological and cytochemical criteria, expressed lymphoid-associated surface antigens. Dual staining of individual blasts demonstrated simultaneous expression of myeloperoxidase (MPO) (including Auer rods) in association with either T-11, CALLA, or terminal deoxynucleotidyl transferase. Blasts from one patient with ANLL demonstrated T cell receptor gene rearrangement, while blasts from another patient demonstrated characteristics associated with T (T-11), B (CALLA and heavy-chain immunoglobulin gene rearrangement), and myeloid (MPO) lineage. There were no consistent cytogenetic abnormalities, and no patient demonstrated independent leukemic clones. Each patient with typical ALL, except for myeloid-associated antigens, achieved complete remission with conventional induction therapy for ALL. By contrast, three of the seven children with ANLL whose blasts expressed the T-11 surface antigen failed ANLL induction therapy. These three patients subsequently achieved remission with ALL therapy.
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Mirro, J., TF Zipf, CH Pui, G. Kitchingman, D. Williams, S. Melvin, SB Murphy i S. Stass. "Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance". Blood 66, nr 5 (1.11.1985): 1115–23. http://dx.doi.org/10.1182/blood.v66.5.1115.bloodjournal6651115.
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The frequency and clinical significance of acute leukemia displaying both lymphoid and myeloid characteristics was determined in 123 consecutive children using a panel of lineage-associated markers. The leukemic blasts from 18 of 95 children (19%) with the diagnosis of acute lymphoblastic leukemia (ALL) by standard diagnostic criteria expressed myeloid-associated cell surface antigens. Despite immunological evidence of lymphoid differentiation (17 CALLA + and one T cell-associated antigen +) and findings of immunoglobulin gene rearrangement, blasts from these patients reacted with one to five monoclonal antibodies identifying myeloid-associated cell surface antigens (My-1, MCS.2, Mo1, SJ-D1, or 5F1). Dual staining with microsphere-conjugated antibodies and analysis by flow cytometry confirmed that some blasts were simultaneously expressing lymphoid- and myeloid-associated antigens. Conversely, blasts from seven of 28 patients (25%) with acute nonlymphocytic leukemia (ANLL), diagnosed by otherwise standard morphological and cytochemical criteria, expressed lymphoid-associated surface antigens. Dual staining of individual blasts demonstrated simultaneous expression of myeloperoxidase (MPO) (including Auer rods) in association with either T-11, CALLA, or terminal deoxynucleotidyl transferase. Blasts from one patient with ANLL demonstrated T cell receptor gene rearrangement, while blasts from another patient demonstrated characteristics associated with T (T-11), B (CALLA and heavy-chain immunoglobulin gene rearrangement), and myeloid (MPO) lineage. There were no consistent cytogenetic abnormalities, and no patient demonstrated independent leukemic clones. Each patient with typical ALL, except for myeloid-associated antigens, achieved complete remission with conventional induction therapy for ALL. By contrast, three of the seven children with ANLL whose blasts expressed the T-11 surface antigen failed ANLL induction therapy. These three patients subsequently achieved remission with ALL therapy.
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Estrov, Z., A. Tawa, XH Wang, ID Dube, H. Sulh, A. Cohen, EW Gelfand i MH Freedman. "In vitro and in vivo effects of deferoxamine in neonatal acute leukemia". Blood 69, nr 3 (1.03.1987): 757–61. http://dx.doi.org/10.1182/blood.v69.3.757.bloodjournal693757.
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A six week old infant with acute leukemia failed to attain remission with chemotherapy. Because we previously demonstrated that the iron chelator deferoxamine (DFO) has antiproliferative properties and modulatory effects on cell differentiation, a protocol was designed for in vitro study and for clinical use in the patient. At diagnosis, blast cells were morphologically undifferentiated, had nondiagnostic cytochemistry, showed an abnormal karyotype (t[4;11]), expressed markers of B cell lineage, and demonstrated C mu gene rearrangement. Tissue culture of marrow or blood cells yielded colonies of leukemic blasts. Increasing concentrations of DFO produced a dose-dependent suppression of patient's blast colony growth in vitro, and blasts within colonies showed a marked change in surface antigen expression from lymphoid to myelomonocytic markers, became monocytic in appearance, and developed intense staining for nonspecific esterase. When DFO was given intravenously to the patient as a single agent for 48 hours, blasts no longer expressed lymphoid antigens and became strongly positive for myelomonocytic markers, identical to the in vitro findings. Intravenous DFO halted rising peripheral blood blast cell numbers and allowed a several-fold increase in normal hematopoietic progenitor colony growth. When combined with low-dose cytosine arabinoside in the treatment protocol, DFO caused striking leukemic cytoreduction. Our findings indicate that DFO has antileukemic properties by virtue of its effects on proliferation and differentiation, and they prompt further experimental and clinical studies with this agent.
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Smadja-Joffe, Florence, Jacques Delaunay, Junyuan Qi, Zeineb Gadhoum, Laetitia Durand Ingeneer i Christine Chomienne. "CD44-Ligation Triggers IL-1, GM-CSF and IL-8 Driven Differentiation Pathways in Human Monoblastic Leukemia Cells." Blood 108, nr 11 (16.11.2006): 4486. http://dx.doi.org/10.1182/blood.v108.11.4486.4486.
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Abstract The CD44 surface antigen is highly expressed on AML cells. We previously reported that its ligation with specific monoclonal antibodies (mAbs) triggers terminal differentiation of leukemic blasts in all AML subtypes. This raised the perspective of developing a CD44-targeted therapy that would be efficient in all AML subtypes, including the monoblastic one (AML-M5) in which, in the absence of specific genetic abnormalities, no targeted therapy is being developed. Here we investigated the molecular mechanism responsible for the CD44-induced differentiation in primary AML-M5 blast samples (n=13). Firstly, by using cDNA arrays, we show that CD44 ligation:activates a burst of cytokine and chemokine genes, through the p38MAPK pathway, indicating that normal CD44 pathways are functional in AML-M5 blasts; andmodulates the gene expression of enzymes, surface proteins and transcription factors as in normal monopoiesis.Secondly, by using functional inhibitors, we demonstrate that the differentiation of CD44-ligated AML-M5 blasts is mediated by IL-1b, GM-CSF and IL-8. These proteins act locally, through an autocrine/paracrine pathway, suggesting that most of the drawbacks often provoked by their systemic injection should be very attenuated. Together, these results provide new support for the development of a CD44-targeted differentiation therapy in acute monoblastic leukemia.
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Forman, M. S., i E. Puré. "T-independent and T-dependent B lymphoblasts: helper T cells prime for interleukin 2-induced growth and secretion of immunoglobulins that utilize downstream heavy chains." Journal of Experimental Medicine 173, nr 3 (1.03.1991): 687–97. http://dx.doi.org/10.1084/jem.173.3.687.
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Resting B cells enlarge, enter the cell cycle, and change their surface phenotype when activated via the surface immunoglobulin (Ig) receptor, but subsequent cell growth and antibody production is relatively limited. To identify stimuli that might prime B cells for enhanced function in vitro, we have compared the effects of anti-Ig with helper T (Th) cells on the formation of B lymphoblasts and the subsequent ability of the blasts to grow and secrete Ig. The B blasts first were induced by either anti-Ig, anti-Ig plus T cell-derived lymphokines, or alloreactive T blasts. Each population of B blasts showed enhanced expression of cell surface adhesion molecules, interleukin 2 receptor (IL-2R) p55, and MHC products, as well as decreased expression of IgD. The allo-activated B blasts were distinctive in expressing low levels of Thy-1 and increased reactivity with peanut agglutinin, a marker of germinal center B blasts in situ. The function of the different populations of B blasts was also different. Whereas anti-Ig or anti-Ig plus lymphokines primed for enhanced responses to lipopolysaccharide (LPS), the B blasts induced by Th cells were insensitive to LPS. B lymphoblasts that had been activated in the presence of helper factors or Th cells responded vigorously to recombinant IL-2 with growth and Ig secretion, and this response was enhanced in the presence of anti-Ig. The B blasts activated directly by Th cells, but not by anti-Ig plus lymphokines, were primed to secrete high levels of IgG1 and IgA. Therefore, the phenotype and function of a B lymphoblast depends upon the manner in which it is primed. When primed by Th cells, IL-2 proves to be the predominant mediator of clonal expansion and antibody secretion.
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Koike, T., S. Aoki, S. Maruyama, M. Narita, T. Ishizuka, H. Imanaka, T. Adachi, H. Maeda i A. Shibata. "Cell surface phenotyping of megakaryoblasts". Blood 69, nr 3 (1.03.1987): 957–60. http://dx.doi.org/10.1182/blood.v69.3.957.957.
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Abstract Surface phenotypic characterization of megakaryoblasts, identified by platelet peroxidase activity, was investigated in four patients who showed increased proliferation of megakaryoblasts: one patient with typical features of acute leukemia, one presenting with acute myelofibrosis, and two with Down's syndrome in whom blasts disappeared spontaneously (transient abnormal myelopoiesis, TAM). MY10 and/or MY9 antigens were expressed on the surface of some megakaryoblasts, but MY7, and MY4, antigens specific to granulocytic or monocytic cells, were not. Some megakaryoblasts were positive for only anti-HLA-DR antibodies. It was speculated that, during the differentiation of the megakaryocytic lineage, MY9 antigen appears transiently on the surface of megakaryoblasts that have lost HLA-DR antigens and have gained the glycoprotein IIb/IIIa antigen. This study also demonstrated that the proliferating blasts in some patients with TAM were mainly megakaryoblasts and suggested that the target cells in TAM are CFU-GEMM.
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Koike, T., S. Aoki, S. Maruyama, M. Narita, T. Ishizuka, H. Imanaka, T. Adachi, H. Maeda i A. Shibata. "Cell surface phenotyping of megakaryoblasts". Blood 69, nr 3 (1.03.1987): 957–60. http://dx.doi.org/10.1182/blood.v69.3.957.bloodjournal693957.
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Surface phenotypic characterization of megakaryoblasts, identified by platelet peroxidase activity, was investigated in four patients who showed increased proliferation of megakaryoblasts: one patient with typical features of acute leukemia, one presenting with acute myelofibrosis, and two with Down's syndrome in whom blasts disappeared spontaneously (transient abnormal myelopoiesis, TAM). MY10 and/or MY9 antigens were expressed on the surface of some megakaryoblasts, but MY7, and MY4, antigens specific to granulocytic or monocytic cells, were not. Some megakaryoblasts were positive for only anti-HLA-DR antibodies. It was speculated that, during the differentiation of the megakaryocytic lineage, MY9 antigen appears transiently on the surface of megakaryoblasts that have lost HLA-DR antigens and have gained the glycoprotein IIb/IIIa antigen. This study also demonstrated that the proliferating blasts in some patients with TAM were mainly megakaryoblasts and suggested that the target cells in TAM are CFU-GEMM.
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Estrov, Z., A. Tawa, XH Wang, ID Dube, H. Sulh, A. Cohen, EW Gelfand i MH Freedman. "In vitro and in vivo effects of deferoxamine in neonatal acute leukemia". Blood 69, nr 3 (1.03.1987): 757–61. http://dx.doi.org/10.1182/blood.v69.3.757.757.
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Abstract A six week old infant with acute leukemia failed to attain remission with chemotherapy. Because we previously demonstrated that the iron chelator deferoxamine (DFO) has antiproliferative properties and modulatory effects on cell differentiation, a protocol was designed for in vitro study and for clinical use in the patient. At diagnosis, blast cells were morphologically undifferentiated, had nondiagnostic cytochemistry, showed an abnormal karyotype (t[4;11]), expressed markers of B cell lineage, and demonstrated C mu gene rearrangement. Tissue culture of marrow or blood cells yielded colonies of leukemic blasts. Increasing concentrations of DFO produced a dose-dependent suppression of patient's blast colony growth in vitro, and blasts within colonies showed a marked change in surface antigen expression from lymphoid to myelomonocytic markers, became monocytic in appearance, and developed intense staining for nonspecific esterase. When DFO was given intravenously to the patient as a single agent for 48 hours, blasts no longer expressed lymphoid antigens and became strongly positive for myelomonocytic markers, identical to the in vitro findings. Intravenous DFO halted rising peripheral blood blast cell numbers and allowed a several-fold increase in normal hematopoietic progenitor colony growth. When combined with low-dose cytosine arabinoside in the treatment protocol, DFO caused striking leukemic cytoreduction. Our findings indicate that DFO has antileukemic properties by virtue of its effects on proliferation and differentiation, and they prompt further experimental and clinical studies with this agent.
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Y B, Madhusudhana, i L. Govindaraju. "Computation of Surface Wave Parameters and Peak Particle Velocity". Journal of Structural Technology 8, nr 2 (21.07.2023): 31–43. http://dx.doi.org/10.46610/jost.2023.v08i02.004.
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In recent times, the rise in terrorist activities has underscored the critical need for designing structures with blast resistance capabilities. However, many Indian codes currently in place do not adequately address the issue of blast loads. This knowledge gap poses a significant challenge to engineers who must ensure the safety and security of structures against such threats. In light of this, the objective of this study is to provide an educational resource to bridge this gap by exploring various methods for calculating blast loads on structures. This paper delves into the subject matter, discussing different methodologies and approaches for estimating blast loads on structures, with a specific focus on the Unified Facilities Criteria (UFC) guidelines. To illustrate the practical application, a numerical example is presented, demonstrating the computation of blast loads on structures using the UFC guidelines. Notably, the results reveal that the surface blast load exhibits an exponential variation along the front wall of the structure. Furthermore, the study introduces the concept of peak particle velocity (PPV) as a parameter for identifying the threshold vibration level that would cause no structural damage. The methodology suggested by the United States Bureau of Mines (USBM) is adopted to calculate the PPV and the corresponding results are presented. By providing insights into blast load computation and the determination of safe vibration levels, this study contributes to enhancing the understanding and preparedness of engineers when it comes to designing structures that can withstand and mitigate the destructive effects of blasts.
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Troeger, Anja, Ludmila Glouchkova, Birgit Ackermann, Gabriele Escherich, Roland Meisel, Hans-Juergen Laws, Helmut Hanenberg i in. "Increased TNF/NGF Receptor Expression on BCP-ALL Blasts Carrying the Prognostically Favorable TEL-AML Rearrangement." Blood 110, nr 11 (16.11.2007): 1431. http://dx.doi.org/10.1182/blood.v110.11.1431.1431.
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Abstract TEL-AML the most common genetic alteration in childhood precursor B (BCP)-ALL is associated with a favorable prognosis yet the underlying mechanism remains largely unknown. Among the tumor necrosis factor (TNF) receptors CD40 is a key regulator of B cell maturation while nerve growth factor receptor (NGFR), CD27 and CD95 have been implicated in cell cycle arrest and blast apoptosis. Here we prospectively assessed baseline surface expression of the different TNF receptors and the costimulatory molecules CD70, CD80 and CD86 on primary BCP-ALL blasts in a pediatric cohort of TEL-AML positive (n=29) and negative patients (pts) (n=89) treated according to the CoALL06-97 protocol. In the TEL-AML positive subgroup, the percentage of blasts positive for CD40 (median; interquartile range: 100%, 100–100% vs. 82%, 56–97%; p<0.001), NGFR (36%, 11–77% vs. 8%, 1–49%; p=0.008) and CD27 (80%, 61–86% vs. 5%, 2–25%; p<0.001) was significantly higher than in the group negative for genetic aberrations such as TEL-AML, BCR-ABL and MLL-AF4. With low to negligible baseline expression for the remaining surface markers, no difference was detected for CD95 (p=0.24), CD70 (p=0.54), CD80 (p=0.87) and CD86 (p=0.06). As signaling via CD40 is known to modulate expression of costimulatory molecules of the TNF receptor/ligand family (CD27 and CD70) and of the IgG superfamily (CD80 and CD86), we compared upregulation of these molecules in TEL-AML positive and negative patients after CD40 crosslinking. To this end blast samples (n=31) were cultured for three days on genetically modified feeder cells expressing CD40 ligand. Although CD80 and CD86 expression was 5- and 3-fold (± 1 and 0.8 SEM) enhanced in CD40-activated blasts (p<0.001), there was no difference in TEL-AML positive and negative patients (CD80: p=0.13; CD86: p=0.17). In contrast there was a significant difference in CD70 upregulation with a 50-fold (± 42 SEM) increase of CD70 positive blasts in the TEL-AML group compared to only a 4.5-fold (± 0.7 SEM) upregulation in TEL-AML negative blasts (p=0.015). Of note as a costimulatory molecule, CD70 is critical not only for activation but particularly for expansion of cytotoxic T cells. CD40-induced upregulation of CD70 was accompanied by 2-fold (± 0.3 SEM) downregulation of initially high baseline expression of CD27 in the TEL-AML positive group only, a phenomenon that is also seen in maturation of normal CD27 positive B cells. In summary our findings provide first evidence for a differential phenotype of TEL-AML positive BCP-ALL blasts with regard to molecules of the TNF receptor/ligand family. Thus TEL-AML positive blasts exhibit a more mature immunophenotype with a significantly higher percentage of CD40, CD27 and NGFR positive blasts at diagnosis potentially contributing to superior survival by enhancing sensitivity towards pro-apoptotic signals via CD27 and NGFR and improving the T cell stimulatory capacity of BCP-ALL blasts by pronounced CD40-dependent upregulation of the costimulatory molecule CD70 critical for sustaining anti-leukemic immune responses.
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Meng, Yuanpei, Yuan He, Chuanting Wang, Yue Ma, Lei Guo, Junjie Jiao i Yong He. "The Effect of Surface Electroplating on Fragment Deformation Behavior When Subjected to Contact Blasts". Materials 16, nr 15 (4.08.2023): 5464. http://dx.doi.org/10.3390/ma16155464.
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Preformed fragments can deform or even fracture when subjected to contact blasts, which might lead to a reduction of the terminal effect. Therefore, to solve this problem, the effect of surface electroplating on the fragment deformation behavior under contact blasts was analyzed. Firstly, blast recovery tests were carried out on uncoated and coated fragments. After the contact blast, the two samples produced different deformation behaviors: the uncoated fragments were fractured, while the coated fragments maintained integrity. The tests were simulated by finite element simulation, and the deformation behavior of the different samples matched well with the test results, which can explain the protective effect of the coating after quantification. In order to further reveal the dynamic behavior involved, detonation wave theory and shock wave transmission theory in solids were used to calculate the pressure amplitude variation at the far-exploding surface of the fragments. The theoretical results showed that the pressure amplitude of the uncoated samples instantly dropped to zero after the shock wave passed through the far-exploding surface, which resulted in the formation of a tensile zone. But the pressure amplitude of the coated samples increased, transforming the tensile zone into the compression zone, thereby preventing the fracture of the fragment near the far-exploding surface, which was consistent with the test and simulated results. The test results, finite element simulations, and theories show that the coating can change the deformation behavior of the fragment and prevent the fracture phenomenon of the fragment. It also prevents the material from missing and a molten state of the fragment in the radial direction by microscopic observation and weight statistics.
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Rauch, Philipp J., Corinne Widmer, Kristin Fritsch, Jana M. Ellegast, Jeroen S. Goede, Peter J. M. Valk, Hitoshi Takizawa i Markus G. Manz. "Mpl Expression on AML Blasts Predicts Cytopenia". Blood 126, nr 23 (3.12.2015): 1387. http://dx.doi.org/10.1182/blood.v126.23.1387.1387.
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Abstract Acute myeloid leukemia (AML) induces profound impairment of healthy hematopoiesis. The production deficit in the bone marrow (BM) leads to development of peripheral anemia, thrombocytopenia and neutropenia, which is a major cause of AML-associated morbidity and mortality. Despite much progress in understanding of AML biology, the mechanisms by which AML blasts interact with elements of normal hematopoiesis to cause cytopenia are unclear. Conventional wisdom has it that blasts infiltrate the marrow and displace normal hematopoiesis. If this concept were to be true, there should be a strong correlation between BM blast count and peripheral cytopenia. Surprisingly, analysis of 223 patients with newly diagnosed AML at a tertiary referral center revealed lack of correlation between initial BM blast count [% of cellularity] and hemoglobin level (ρ=-0.11, P=0.12), platelet count (ρ=-0.00, P=0.53) and absolute neutrophil count (ρ=0.13, P=0.06). This indicates that mechanisms other than displacement of normal hematopoiesis dictate the severity of cytopenia in AML patients. Hematopoiesis is tightly regulated by cytokines. Among them, thrombopoietin (TPO) acts through its receptor c-Mpl as the master regulator of megakaryopoiesis, but also exerts upstream effects on hematopoietic stem and progenitor cells (HSPC). TPO levels are controlled by receptor-mediated scavenging by cells carrying c-Mpl on the surface, with platelets representing the lion's share in a healthy organism. This negative feedback loop results in strong negative correlation between serum TPO concentration and platelet count in the steady state. When we examined this relationship in our AML cohort, TPO levels did not follow the expected negative correlation with platelet counts (ρ=-0.10, P=0.59). Comparison with historic controls with thrombocytopenia induced by chemotherapy for non-hematopoietic malignancy revealed that the lack of correlation was driven by AML cases with severe thrombocytopenia that had lower than expected levels of TPO in the serum. As HSPC are known to express c-Mpl, we hypothesized that HSPC-derived AML blasts may also express the receptor and cause insufficiency of hematopoiesis by means of receptor-mediated TPO scavenging. To test this hypothesis, we compared c-Mpl expression on blasts in AML cases with severe thrombocytopenia and low TPO concentration (potential scavenger cases) to cases with TPO levels adequate for the degree of cytopenia. Both surface flow cytometry and qPCR demonstrated higher c-Mpl expression in potential scavenger cases (3.1-fold, P=0.02). To determine whether this difference in expression translates into increased serum TPO clearance, we incubated AML blasts with high (c-Mpl+) and low (c-Mpl-) receptor expression in serum containing recombinant human TPO at a concentration of 100 pg/mL. After 2h, TPO clearance reached 45 pg per 106 cells in wells with c-Mpl+ blasts, compared to only 4 pg per 106 cells in wells with c-Mpl- blasts (P=0.02). This confirms the hypothesis that AML blasts can lower TPO levels by virtue of their c-Mpl expression. Validation studies in an independent, multi-center Dutch-Belgian-Swiss cohort of 437 AML cases confirmed lack of correlation between initial BM blast count and cytopenia. Ranked gene list correlation analysis of whole genome microarray data proved significant enrichment of the MPL transcript in patients with severe thrombocytopenia when compared to patients with average platelet counts (rank 27/20'589, FDR<10-6). MPL enrichment could also be observed in patients with severe neutropenia (P<0.01), but there was no correlation between MPL transcript level and degree of anemia. Lastly, we asked if MPL expression was related to cytogenetic or molecular AML subtype: indeed, microarray analysis showed higher MPL expression in cases of AML with t(8;21) than in any other subtype (P<10-4). Concurrently, these patients displayed significantly lower platelet count (40 vs 83 x 109/L, P=0.02) when compared to all other AML cases. In summary, our study demonstrates that cytopenia in AML is independent of BM blast count, but strongly correlated with c-Mpl expression on blasts. We show that c-Mpl+ blasts clear TPO, causing insufficient TPO levels and contributing to development of thrombocytopenia and neutropenia. The work may have important ramifications for treatment of AML-induced cytopenia, especially in the relapsed or refractory setting. Disclosures No relevant conflicts of interest to declare.
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Ritchie, D., Paul Neeson, Michael V. Berridge i Patries Herst. "The Level of Glycolytic Metabolism of AML Blasts May Predict Drug Sensitivity and Prognosis in Patients with AML". Blood 112, nr 11 (16.11.2008): 4022. http://dx.doi.org/10.1182/blood.v112.11.4022.4022.
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Abstract Solid tumors that show high levels of glycolysis are often refractory to therapies such as arsenic trioxide (ATO), which mediate their anti-tumor effect via increased mitochondrial free radical formation. We have previously shown that purely glycolytic, mitochondrial gene knock-out HL60r0 cells were significantly more resistant to apoptosis induced by combined ATRA+ATO treatment than non-glycolytic HL60 cells [Herst et al. Leuk Res 2008]. Here, we investigate whether the degree of glycolytic metabolism of AML blasts isolated from diagnostic bone marrow samples reflects in vitro drug sensitivity and duration of remission from AML. Following Ethics Committee approval, AML blasts from 22 patient bone marrow (BM) samples were isolated from bone marrow aspirates previously stored in the Peter MacCallum Cancer Centre tissue bank. On each sample of AML blasts we determined the level of glycolytic metabolism by % FCCP-inhibition of reduction of the water-soluble tetrazolium dye, WST-1/PMS at the cell surface [Herst, Biochim Biophys Acta, 2007] and compared results to those measured for several cell lines and 8 primary bone marrow samples of acute lymphoblastic leukemia (ALL). In samples where sufficient (>105) cells were available, we separately assessed the degree of blast apoptosis, via annexin V/propidium iodide staining and flow cytometric analysis, induced by a 72 hour culture in either 1mM all-trans retinoic acid (ATRA), 2mM ATO or combined 1mM ATRA+2 mM ATO. Analysis of glycolysis revealed that AML blast samples distributed into two non-overlapping groups (p=0.0001) of moderate (n=13) and high levels (n=9) of glycolytic metabolism. In contrast, the level of glycolytic metabolism in ALL blasts, normal donor peripheral blood T cells and several cancer cell lines (HL60, Hela, HeLaS3w, BW1100., EL4, A20) varied extensively (Figure 1A). Paired samples of both diagnosis and subsequent relapse BM were available from 3 patients with >80% blasts in both samples. In these paired samples the level of glycolytic metabolism did not alter (all moderately glycolytic at both time points) from diagnosis to relapse, suggesting that this is a stable metabolic feature of AML that is not modified, or selected by, exposure to prior chemotherapy. Highly glycolytic AML blasts were relatively resistant to combined ATRA and ATO treatment than moderately glycolytic blasts (p=0.025) but not to ATRA or ATO treatment alone (Figure 1B). Survival from the date of bone marrow sampling was also assessed and compared between high and moderate glycolytic cohorts. At the time of analysis, with a median follow up of 4 years, 6 out of 9 patients with highly glycolytic AML blasts remain alive. Conversely, all 13 patients with moderately glycolytic AML blasts have died of progressive disease, with median survival of 64 days (p=0.005 by Gehan- Breslow-Wilcoxon test). Our results suggest that the extent of glycolytic metabolism, as measured by % FCCP-inhibition of dye reduction may be used to identify chemo-refractory and chemo-sensitive subgroups of AML and may be potentially applicable in identifying patients who may benefit from treatment intensification or novel therapies. Figure 1: The effect of the extent of glycolytic metabolism on drug sensitivity of leukemic blasts. A. The extent of glycolytic metabolism in different cell types as determined by the % FCCP-inhibition of PMET. Values for individual BM samples, and averages of at least 3 separate experiments for resting T cells: 10, activated T cells: 63, normal BM: 62, HL60r0: 100, HeLaS3 r0: 99, HeLa r0: 98, BW1199: 74, EL4: 48, A20: 45, Molt-4: 30, HeLaS3: 37, U226: 6, HL60L 2, HeLa: 1, RPMI8226: 0. * p=0.0001 between highly glycolytic (n= 9) and moderately glycolytic (n= 13) AML blasts. B. Sensitivity of AML blasts to ATRA, ATO and combined ATRA+ATO, measured as [% viable blast after treatment]/[% viable blasts in controls]. Results are presented as average ± SEM of 4 highly glycolytic AML blasts (black bars) and 5 moderately glycolytic AML blasts (grey bars). * p=0.025 Figure 1:. The effect of the extent of glycolytic metabolism on drug sensitivity of leukemic blasts. A. The extent of glycolytic metabolism in different cell types as determined by the % FCCP-inhibition of PMET. Values for individual BM samples, and averages of at least 3 separate experiments for resting T cells: 10, activated T cells: 63, normal BM: 62, HL60r0: 100, HeLaS3 r0: 99, HeLa r0: 98, BW1199: 74, EL4: 48, A20: 45, Molt-4: 30, HeLaS3: 37, U226: 6, HL60L 2, HeLa: 1, RPMI8226: 0. * p=0.0001 between highly glycolytic (n= 9) and moderately glycolytic (n= 13) AML blasts. B. Sensitivity of AML blasts to ATRA, ATO and combined ATRA+ATO, measured as [% viable blast after treatment]/[% viable blasts in controls]. Results are presented as average ± SEM of 4 highly glycolytic AML blasts (black bars) and 5 moderately glycolytic AML blasts (grey bars). * p=0.025
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Uckun, FM, NK Ramsay, KG Waddick, W. Jaszcz, M. Chandan-Langlie, V. Obuz, R. Haake, K. Gajl-Peczalska, JH Kersey i CW Song. "In vitro and in vivo radiation resistance associated with CD3 surface antigen expression in T-lineage acute lymphoblastic leukemia". Blood 78, nr 11 (1.12.1991): 2945–55. http://dx.doi.org/10.1182/blood.v78.11.2945.2945.
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Abstract The radiobiologic features of primary clonogenic blasts (referred to also as T-lineage leukemic progenitor cells) from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia (ALL) patients were analyzed. Intrinsic radiation sensitivity differed substantially among primary clonogenic blasts from 34 newly diagnosed patients. The mean D0 (37% dose slope), SF2 (surviving fraction at 200 cGy), and alpha values (initial slope of the survival curve) were 141 +/- 15 cGy, 0.31 +/- 0.04, and 0.630 +/- 0.093 Gy-1, respectively. Among newly diagnosed cases, nine had SF2 values of greater than or equal to 0.50 and alpha values of less than or equal to 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic blasts using the multitarget and linear quadratic models of cell survival. Of these nine radiation resistant cases, seven were CD3+. Furthermore, the mean D0 (162 +/- 20.8 cGy) and SF2 (0.377 +/- 0.057) values for the 20 CD3+ cases were significantly higher than the D0 (108.6 +/- 18.2 cGy) and SF2 (0.204 +/- 0.051) values for the 14 CD3- cases (P less than or equal to .05). Thus, clonogenic blasts from CD3+ newly diagnosed T- lineage ALL patients were more resistant to radiation than clonogenic blasts from CD3- newly diagnosed T-lineage ALL patients. Nineteen T- lineage ALL patients received autologous bone marrow transplants during complete remission. Pretransplant conditioning consisted of total body irradiation (TBI) combined with high-dose chemotherapy. Primary clonogenic blasts from patients who relapsed after bone marrow transplantation (BMT) displayed a particularly high degree of intrinsic radiation resistance with a mean D0 value of 333 cGy and an alpha value of 0.112 Gy-1. The expression of CD3 antigen appeared to predict the outcome of relapsed T-lineage ALL patients undergoing autologous BMT after TBI plus high-dose chemotherapy. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission after BMT were 60% +/- 22% (mean relapse - free interval = 1.6 +/- 0.7 years) for CD3- patients and 0% +/- 0% (mean relapse - free interval = 0.2 +/- 0.0 years) for CD3+ patients (P = .002). Furthermore, the mean percentage of CD3-positive leukemic marrow blasts at presentation or relapse before BMT was significantly lower than the mean percentage of CD3- positive leukemic marrow blasts at relapse after BMT. Notably, in cultured leukemic bone marrow specimens from newly diagnosed as well as relapsed patients, colony blasts surviving in vitro radiation expressed CD3 more vividly than did colony blasts in unirradiated cultures.(ABSTRACT TRUNCATED AT 400 WORDS)
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Uckun, FM, NK Ramsay, KG Waddick, W. Jaszcz, M. Chandan-Langlie, V. Obuz, R. Haake, K. Gajl-Peczalska, JH Kersey i CW Song. "In vitro and in vivo radiation resistance associated with CD3 surface antigen expression in T-lineage acute lymphoblastic leukemia". Blood 78, nr 11 (1.12.1991): 2945–55. http://dx.doi.org/10.1182/blood.v78.11.2945.bloodjournal78112945.
Pełny tekst źródłaStreszczenie:
The radiobiologic features of primary clonogenic blasts (referred to also as T-lineage leukemic progenitor cells) from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia (ALL) patients were analyzed. Intrinsic radiation sensitivity differed substantially among primary clonogenic blasts from 34 newly diagnosed patients. The mean D0 (37% dose slope), SF2 (surviving fraction at 200 cGy), and alpha values (initial slope of the survival curve) were 141 +/- 15 cGy, 0.31 +/- 0.04, and 0.630 +/- 0.093 Gy-1, respectively. Among newly diagnosed cases, nine had SF2 values of greater than or equal to 0.50 and alpha values of less than or equal to 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic blasts using the multitarget and linear quadratic models of cell survival. Of these nine radiation resistant cases, seven were CD3+. Furthermore, the mean D0 (162 +/- 20.8 cGy) and SF2 (0.377 +/- 0.057) values for the 20 CD3+ cases were significantly higher than the D0 (108.6 +/- 18.2 cGy) and SF2 (0.204 +/- 0.051) values for the 14 CD3- cases (P less than or equal to .05). Thus, clonogenic blasts from CD3+ newly diagnosed T- lineage ALL patients were more resistant to radiation than clonogenic blasts from CD3- newly diagnosed T-lineage ALL patients. Nineteen T- lineage ALL patients received autologous bone marrow transplants during complete remission. Pretransplant conditioning consisted of total body irradiation (TBI) combined with high-dose chemotherapy. Primary clonogenic blasts from patients who relapsed after bone marrow transplantation (BMT) displayed a particularly high degree of intrinsic radiation resistance with a mean D0 value of 333 cGy and an alpha value of 0.112 Gy-1. The expression of CD3 antigen appeared to predict the outcome of relapsed T-lineage ALL patients undergoing autologous BMT after TBI plus high-dose chemotherapy. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission after BMT were 60% +/- 22% (mean relapse - free interval = 1.6 +/- 0.7 years) for CD3- patients and 0% +/- 0% (mean relapse - free interval = 0.2 +/- 0.0 years) for CD3+ patients (P = .002). Furthermore, the mean percentage of CD3-positive leukemic marrow blasts at presentation or relapse before BMT was significantly lower than the mean percentage of CD3- positive leukemic marrow blasts at relapse after BMT. Notably, in cultured leukemic bone marrow specimens from newly diagnosed as well as relapsed patients, colony blasts surviving in vitro radiation expressed CD3 more vividly than did colony blasts in unirradiated cultures.(ABSTRACT TRUNCATED AT 400 WORDS)
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Nawar, Mahmoud, Alaa Ata, Marwa Nabil i Sally Hassan. "Numerical analysis of underground tunnels subjected to surface blast loads". Frattura ed Integrità Strutturale 15, nr 55 (28.12.2020): 159–73. http://dx.doi.org/10.3221/igf-esis.55.12.
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The increased terrorist attacks on important public structures and utilities have raised the vital necessity for the investigation of performance of structures under blast loads to improve the design and enhance the behavior of structures subjected to such threats. In this study, 3-D finite element analysis is used to study the effect of surface explosions on the response of RC bored tunnels. The soil behavior is modelled using Drucker-Prager Cap model. Two types of soil are investigated, and the blast load is considered through various weights of TNT explosive charges at heights of 0.50 m and 1.0 m from ground surface. To study the effect of horizontal standoff distance, six different horizontal distances are considered. The results show that the soil type has a significance effect on tunnel response due to surface blasts. Also the weight and the location of charge have a great effect on the safety of the tunnel. Finally, a parametric study is established to define the borders of the restricted area around the tunnel location to be safe.
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Bonalumi, Pamela, Matteo Colombo, Cesare Comina, Marco di Prisco, Sebastiano Foti i Andrea Galli. "Characterization of Blast Effects on Surrounding Soil: Internal Detonations in Underground Pipes". Applied Mechanics and Materials 82 (lipiec 2011): 302–7. http://dx.doi.org/10.4028/www.scientific.net/amm.82.302.
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Preliminary results from a series of blast tests within a buried pipeline are reported. The paper is mainly focused on the characterization of the site, providing an insight into the effects of different basting events in terms of soil mechanical parameters. The blasts have been monitored by means of accelerometers embedded in the ground and placed on the ground surface. The recorded acceleration time histories show a strong attenuation as the wave travels away from the source.
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Ho, Jenny M., Stephanie M. Dobson, Jessica McLeod, Veronique Voisin, Alex Murison, James Kennedy, Sasan Zandi i in. "Isolation of CD34− and CD34+ Leukemia Stem Cells from Acute Myeloid Leukemia Blasts Using CD200". Blood 132, Supplement 1 (29.11.2018): 2790. http://dx.doi.org/10.1182/blood-2018-99-119318.
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Abstract Therapy resistance and relapse in acute myeloid leukemia (AML) are driven by leukemia stem cells (LSCs). Recent evidence highlighting functional and genetic heterogeneity among LSC subclones underscores the importance of capturing the entire LSC compartment in studies of LSC biology. Although LSCs are often enriched in the CD34+CD38- cell fraction, they are frequently detected in other phenotypic fractions, and in some cases are restricted to the CD34- population. In order to discover novel LSC markers, we examined genes differentially expressed between functionally-validated LSC+ and LSC- cell fractions obtained from primary AML samples, and identified CD200 as a candidate cell surface marker for LSCs. CD200 expression in 57 primary AML samples was analyzed by flow cytometry using anti-human CD200 clone 1B9(kindly provided by Trillium Therapeutics Inc.). CD200 was present on a greater proportion of CD45dim blasts compared to more differentiated CD45high non-blast populations (54.4% versus 21.7%, p<0.0001); CD200+ cells often represented a distinct blast population. Overall there was a positive but non-linear correlation (R2=0.46, p<0.0001) between CD34 and CD200 expression; the proportion of CD200+ blasts was significantly greater than that of CD34+ blasts in samples with low to intermediate CD34 expression. In AMLs where CD34 expression was lower than CD200, CD34 was present on a subset of CD200+ blasts; accordingly, CD200+ blasts comprised variable proportions of CD34- and CD34+ cells. These observations suggest that CD200 expression on blasts could be a better marker for LSCs than CD34. To validate CD200 as a LSC marker, leukemic blasts were sorted from 15 primary AML samples based on CD45 and CD200 expression and transplanted into NSG mice. Samples were selected based on either the presence of both CD200+ and CD200- blasts, or CD200 expression on <5% of mononuclear cells (MNCs). In 8 of 15 AMLs, LSCs were enriched within the CD200+ fraction (termed CD200+ LSCs). In 4 of these cases, LSCs comprised both CD34- and CD34+ cells, but the entire LSC compartment was captured within the CD200+ blast population. Limiting dilution studies showed that CD200 expression enriched for CD200+ LSCs by up to 20-fold. In 6 of the remaining samples, LSCs resided in the CD200- fraction (termed CD200- LSCs), while in one sample, LSCs were present in both CD200+ and CD200- fractions. In AMLs with CD200- LSCs, CD200 was expressed on <5% of MNCs and <5% of blasts, in contrast to AMLs with CD200+ LSCs where CD200 expression on MNCs was variable (3% to 85%) and >5% on blasts. Overall, these results indicate that CD200 expression can be used to segregate LSCs from bulk leukemia cells. CD200 expression may be a particularly useful LSC marker in cytogenetically normal AMLs with NPM1 mutation (CN-AMLNPM1c), which have low or negative CD34 expression and commonly possess CD34- LSCs. Among 20 CN-AMLNPM1c samples, the proportion of CD200+ blasts was higher than that of CD34+ blasts irrespective of FLT3-ITD status, although there was a trend towards higher CD200 expression in FLT3-ITD+ samples. In xenotransplantation assays, 7 of 8 CN-AMLNPM1c samples tested contained CD200+ LSCs while the remaining sample contained both CD200+ and CD200- LSCs. Principal component analysis of gene expression profiles demonstrated that functionally-validated CD200+ LSC-containing fractions from CN-AMLNPM1c patients clustered separately from LSC fractions from NPM1wt or cytogenetically-abnormal cases, and were enriched for stem cell genes by gene set enrichment analysis. Furthermore, ATAC-Seq analysis demonstrated greater chromatin accessibility in CD200+ LSC-containing versus CD200‒ LSC-depleted fractions from CN-AMLNPM1c patients, with unique enrichment of HOX motifs. These data validate CD200 as an LSC marker in CN-AMLNPM1c cases. In summary, CD200 is a valuable tool for capturing heterogeneous LSC populations including both CD34+ and CD34- LSCs in many primary AML samples. It will be particularly useful for future studies of LSCs in CN-AMLNPM1c where CD34 expression does not identify LSCs. Disclosures No relevant conflicts of interest to declare.
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Uckun, F. M., K. J. Gajl-Peczalska, J. H. Kersey, L. L. Houston i D. A. Vallera. "Use of a novel colony assay to evaluate the cytotoxicity of an immunotoxin containing pokeweed antiviral protein against blast progenitor cells freshly obtained from patients with common B-lineage acute lymphoblastic leukemia." Journal of Experimental Medicine 163, nr 2 (1.02.1986): 347–68. http://dx.doi.org/10.1084/jem.163.2.347.
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We report a novel colony assay for B-lineage progenitor cells in acute lymphoblastic leukemia (ALL). The primary plating efficiency of blast progenitors freshly obtained from common B-lineage ALL patients varied between 0.09 and 2.63%. Morphological, cytochemical, and immunological analyses of cells from day 7 colonies provided the evidence that they are B-lineage lymphoblasts. Immunological marker analyses of cultured blasts using BA-2 (anti-CD9), BA-3 (anti-CD10), BA-1 (anti-CD24), and B43 mAb have allowed us to define two distinct immunological groups. The first group had BA-2+, BA-3+, BA-1+, B43+ marker profiles, consistent with the phenotype of uncultured bone marrow blasts. The second group differed in that the cells in the blast colonies were BA-3 (anti-CD10)-negative, although many of the cells in the bulk population were BA-3+ before culture. Blasts from both groups were able to proliferate and form secondary colonies when recultured. A pan-B immunotoxin was synthesized by linking B43, a human B cell-specific mAb, to pokeweed antiviral protein (PAP). This study showed that B43-PAP can effectively eradicate leukemic progenitor cells freshly obtained from patients with common B-lineage ALL. B43-PAP eliminated greater than 99.96% of blast progenitors under conditions in which only minimal inhibition of normal bone marrow progenitor cells (CFU-GM, CFU-E, CFU-MK, CFU-GEMM) was observed. Our results establish that the surface determinant recognized by B43 is expressed on B-lineage progenitor cells in ALL, and that these cells are sensitive to PAP at the ribosomal level. To our knowledge, B43-PAP is the first IT to prove effective against common B-lineage ALL cells.
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Troeger, Anja, Ingo Schmitz, Ludmila Glouchkova, Meinolf Siepermann, Gritta Janka-Schaub, Klaus Schulze-Osthoff i Dagmar Dilloo. "Upregulation of FLIPs upon CD40 Stimulation - A Novel Inhibititory Mechanism of CD95-Induced Apoptosis in Precursor B-ALL Blasts in Children." Blood 106, nr 11 (16.11.2005): 855. http://dx.doi.org/10.1182/blood.v106.11.855.855.
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Abstract The influence of the microenvironment on the activation status and behaviour of ALL blasts is critical for interactions with the immune system in vivo. The capacity of B cells to respond to CD40-ligand (CD40L) stimulation is critical for their sensitisation to immunological control mechanisms and susceptibility to apoptotic signals. Primary precursor B-ALL blasts (BCP-ALL; n=32) lack CD95-expression (mean±SE; 4.2±0.6% positive cells) and are resistant to apoptosis while significant up-regulation of CD95 is apparent upon CD40-stimulation in BCP-ALL blasts that reaches a plateau after 72 h. Yet, in spite of equivalent CD95-upregulation in ALL blasts (58.3±6.5%; n=17) and normal B cells (59.3±13.1%) specific apoptosis is markedly lower in ALL compared to mature B cells (19.1±3% vs 36.7±5.5%). Resistance to apoptosis in ALL blasts and its reversibility after cycloheximid treatment suggest that anti-apoptotic mechanisms prevent induction of cell death via CD95 ligation in CD40 activated blasts. In accordance, in CD40-activated ALL blasts caspase 8 and 3 activity is not enhanced upon CD95 ligation in contrast to an 1.8±0.3 and 1.7±0.3 fold increase in caspase activity in stimulated normal B cells (n=7), suggesting a block of the apoptotic cascade in BCP-ALLrelatively close to the receptor level. CD40L-activated ALL blasts and normal B cells were submitted to western blot analysis with respect to the molecules associated to the death-inducing signalling complex (DISC). FADD and the zymogen form of caspase-8 are constitutively expressed in both malignant and non malignant B cells with no modulation following CD40 ligation. In contrast, the anti-apoptotic short isoform of the c-FLICE inhibitory protein FLIPS is weakly expressed in naïve blasts and B cells, but strongly up-regulated upon 72h CD40-ligation in ALL with only barely detectable levels in CD40-activated normal B cells. We therefore propose, that prolonged induction of the FLIPS expression inhibits the onset of apoptosis despite high CD95 surface expression levels in BCP-ALL blasts. As an additional anti-apoptotic mechanism inhibiting the downstream effector caspases we demonstrated significant upregulation of the inhibitor of apoptosis protein (IAP) survivin in CD40-activated BCP-ALL (n=6) compared to the unstimulated control (632pg/ml±200pg/ml vs 180pg/ml±52pg/ml). Thus, we identified FLIPS as a CD40-regulated upstream anti-apoptotic element and concomitant downstream upregulation of survivin protein expression as critical mechanisms contributing to blast cell resistance to apoptosis.
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Budel, LM, IP Touw, R. Delwel i B. Lowenberg. "Granulocyte colony-stimulating factor receptors in human acute myelocytic leukemia". Blood 74, nr 8 (1.12.1989): 2668–73. http://dx.doi.org/10.1182/blood.v74.8.2668.2668.
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Abstract The binding of granulocyte colony-stimulating factor (G-CSF) to normal and human acute myeloid leukemia (AML) cells was investigated with radiolabeled recombinant human G-CSF (rhG-CSF). In all 14 cases of primary AML specific receptors for G-CSF were demonstrated on purified blast cells. The average numbers of G-CSF receptors ranged from very low to 428 receptors per cell (mean). Normal granulocytes showed G-CSF binding sites on their surface at higher densities (703 to 1,296 sites per cell). G-CSF receptors appeared to be of a single affinity type with a dissociation constant (kd) ranging between 214 and 378 pmol/L for AML blasts and 405 to 648 pmol/L for granulocytes. In 12 of 14 cases, including those with relatively low specific binding, G-CSF was a potent inducer of DNA synthesis of blasts in vitro; therefore, apparently relatively few receptors are required to permit activation of AML cell growth. However, in two cases cell cycling was not activated in response to G-CSF despite G-CSF receptor availability. The results show that G-CSF receptors of high affinity are frequently expressed on the blasts of human AML, but their presence may not be a strict indicator of the proliferative responsiveness of the cells to G- CSF.
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Budel, LM, IP Touw, R. Delwel i B. Lowenberg. "Granulocyte colony-stimulating factor receptors in human acute myelocytic leukemia". Blood 74, nr 8 (1.12.1989): 2668–73. http://dx.doi.org/10.1182/blood.v74.8.2668.bloodjournal7482668.
Pełny tekst źródłaStreszczenie:
The binding of granulocyte colony-stimulating factor (G-CSF) to normal and human acute myeloid leukemia (AML) cells was investigated with radiolabeled recombinant human G-CSF (rhG-CSF). In all 14 cases of primary AML specific receptors for G-CSF were demonstrated on purified blast cells. The average numbers of G-CSF receptors ranged from very low to 428 receptors per cell (mean). Normal granulocytes showed G-CSF binding sites on their surface at higher densities (703 to 1,296 sites per cell). G-CSF receptors appeared to be of a single affinity type with a dissociation constant (kd) ranging between 214 and 378 pmol/L for AML blasts and 405 to 648 pmol/L for granulocytes. In 12 of 14 cases, including those with relatively low specific binding, G-CSF was a potent inducer of DNA synthesis of blasts in vitro; therefore, apparently relatively few receptors are required to permit activation of AML cell growth. However, in two cases cell cycling was not activated in response to G-CSF despite G-CSF receptor availability. The results show that G-CSF receptors of high affinity are frequently expressed on the blasts of human AML, but their presence may not be a strict indicator of the proliferative responsiveness of the cells to G- CSF.
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Landolfi, N. F., R. R. Rich i R. G. Cook. "Differential glycosylation requirements for the cell surface expression of class I molecules." Journal of Immunology 134, nr 1 (1.01.1985): 423–30. http://dx.doi.org/10.4049/jimmunol.134.1.423.
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Abstract The importance of asparagine-linked glycosylation in the cell surface expression of several class I molecules was examined. C57BL/6 (B6) T cell blasts were treated with tunicamycin (TM), an antibiotic that inhibits N-linked glycosylation. The levels of various class I molecules on these cells were examined by flow cytometry and were compared to the levels of the same molecules on untreated cells. A 12-hr TM treatment did not significantly alter the levels of H-2Kb, Db, or Qa-2; however, such treatment decreased the surface expression of the Qa-1b allelic product to undetectable levels. A time-course study indicated that a decrease in the level of Qa-1.2 expression was apparent after only 4 hr of TM treatment. An examination of T cell blasts prepared from mouse strains possessing the Qa-1a, Qa-1c, and Qa-1d alleles indicated that all allelic products of this locus demonstrated a marked decrease in cell surface expression on TM treatment, whereas other class I molecules (H-2Ks, TL) exhibited slight or no decrease. Two-dimensional polyacrylamide gel electrophoresis analysis of immunoprecipitates from detergent lysates of surface-iodinated TM-treated B6 blasts revealed the presence of the unglycosylated form of the H-2Kb molecule on the cell surface. No such form of the Qa-1.2 molecule could be detected by similar analysis. To establish that the above observations were not simply a result of the inability of the Qa-1-specific alloantisera to react with the unglycosylated Qa-1 molecule, lysates of surface-iodinated B6 blasts were digested with endoglycosidase F, which cleaves N-linked carbohydrate moieties. Immunoprecipitation analysis indicated that the antisera could react with the unglycosylated form of the Qa-1 molecule. These results indicate that N-linked glycosylation has differential importance in the cell surface expression of class I molecules.
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Moingeon, P., A. Ythier, A. Nowill, L. Delmon, C. Bayle, JL Pico, C. Bohuon i T. Hercend. "Short-term culture of acute myeloid leukemia blasts: analysis of acquired susceptibility to activated natural killer cells". Blood 67, nr 3 (1.03.1986): 777–83. http://dx.doi.org/10.1182/blood.v67.3.777.777.
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Abstract Following a cryopreservation step, short-term cultures of circulating leukemic blasts from a patient with acute myeloid leukemia (AML) were performed. Because cultured tumor cells became susceptible to natural killer (NK) activity, in vitro alteration of the blasts was studied. Immediately after thawing, cell suspensions consisted of a relatively homogeneous population of undifferentiated blasts. In culture, tritiated thymidine uptake by the leukemic cells was low during the first 24 hours and then increased (X20) to a peak on day 7. The cell concentration started to increase on day 4. On day 8, less than 10% of the cultured cells still appeared as undifferentiated blasts, whereas up to 60% were granular and 30% to 40% had a monocytoid morphology. Prior to being cultured, the blasts were resistant to resting and IL2- activated natural killing. When the kinetics of in vitro acquired susceptibility were studied, it was found that maximum cytotoxicity against these leukemic cells was reached within 24 hours. Thus, the blasts had become NK-sensitive prior to increase in DNA synthesis, proliferation, and differentiation based on morphological and cytochemical criteria. In contrast, there was a positive correlation between acquired susceptibility and surface expression of an activation antigen, termed TNKtar. To dissect further the mechanisms of acquired susceptibility, a series of six NK clones representing four distinct phenotypes of NK active lymphocytes were tested against the leukemic cells. Immediately after thawing, blasts were essentially resistant to all clones, whereas they were strongly killed by 5 of 6 clones when cultured for 24 hours. Cold target inhibition assays indicated that resistance of fresh blasts was likely to be due to a binding defect. These results suggested that tumor cells became susceptible because they surface-expressed NK target structure(s) in the early phase of an activation process leading to their proliferation and/or differentiation. This hypothesis was substantiated for one clone, termed JT9, because the anti-TNKtar antibody blocked cytotoxicity of JT9 cells against the cultured blasts.
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Moingeon, P., A. Ythier, A. Nowill, L. Delmon, C. Bayle, JL Pico, C. Bohuon i T. Hercend. "Short-term culture of acute myeloid leukemia blasts: analysis of acquired susceptibility to activated natural killer cells". Blood 67, nr 3 (1.03.1986): 777–83. http://dx.doi.org/10.1182/blood.v67.3.777.bloodjournal673777.
Pełny tekst źródłaStreszczenie:
Following a cryopreservation step, short-term cultures of circulating leukemic blasts from a patient with acute myeloid leukemia (AML) were performed. Because cultured tumor cells became susceptible to natural killer (NK) activity, in vitro alteration of the blasts was studied. Immediately after thawing, cell suspensions consisted of a relatively homogeneous population of undifferentiated blasts. In culture, tritiated thymidine uptake by the leukemic cells was low during the first 24 hours and then increased (X20) to a peak on day 7. The cell concentration started to increase on day 4. On day 8, less than 10% of the cultured cells still appeared as undifferentiated blasts, whereas up to 60% were granular and 30% to 40% had a monocytoid morphology. Prior to being cultured, the blasts were resistant to resting and IL2- activated natural killing. When the kinetics of in vitro acquired susceptibility were studied, it was found that maximum cytotoxicity against these leukemic cells was reached within 24 hours. Thus, the blasts had become NK-sensitive prior to increase in DNA synthesis, proliferation, and differentiation based on morphological and cytochemical criteria. In contrast, there was a positive correlation between acquired susceptibility and surface expression of an activation antigen, termed TNKtar. To dissect further the mechanisms of acquired susceptibility, a series of six NK clones representing four distinct phenotypes of NK active lymphocytes were tested against the leukemic cells. Immediately after thawing, blasts were essentially resistant to all clones, whereas they were strongly killed by 5 of 6 clones when cultured for 24 hours. Cold target inhibition assays indicated that resistance of fresh blasts was likely to be due to a binding defect. These results suggested that tumor cells became susceptible because they surface-expressed NK target structure(s) in the early phase of an activation process leading to their proliferation and/or differentiation. This hypothesis was substantiated for one clone, termed JT9, because the anti-TNKtar antibody blocked cytotoxicity of JT9 cells against the cultured blasts.
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Smith, FO, C. Rauch, DE Williams, CJ March, D. Arthur, J. Hilden, BC Lampkin i in. "The human homologue of rat NG2, a chondroitin sulfate proteoglycan, is not expressed on the cell surface of normal hematopoietic cells but is expressed by acute myeloid leukemia blasts from poor-prognosis patients with abnormalities of chromosome band 11q23". Blood 87, nr 3 (1.02.1996): 1123–33. http://dx.doi.org/10.1182/blood.v87.3.1123.bloodjournal8731123.
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In our efforts to produce monoclonal antibodies that recognize cell- surface antigens expressed by hematopoietic precursor and stromal cells, we generated a monoclonal antibody, 7.1, which recognizes a 220- to 240-kD cell-surface protein whose N-terminal amino acid sequence is identical to the rat NG2 chondroitin sulfate proteoglycan molecule. This chondroitin sulfate proteoglycan, previously reported to be expressed by human melanoma cells, was not found to be expressed by normal hematopoietic cells, nor was it expressed on the cell surface of cell lines of hematopoietic origin including cell lines with 11q23 abnormalities. It was found on the cell surface of acute myeloid leukemia (AML) blasts and cell lines derived from nonhematopoietic tissues. Samples of leukemic marrow from 166 children with AML enrolled on Childrens Cancer Group protocol 213 were evaluated for cell-surface expression of this proteoglycan molecule. In 18 of 166 (11%) patient samples, greater than 25% of leukemic blasts expressed the NG2 molecule. These 18 patients had a poorer outcome with respect to survival (P = .002) and event-free survival (P = .035) with an actuarial survival at 4 years of 16.7%. Blast cell expression of the NG2 molecule was strongly associated with French-American-British M5 morphology (P < .0001) and abnormalities in chromosome band 11q23, site of the MLL gene. These results show that the NG2 molecule is expressed by malignant hematopoietic cells that have abnormalities in chromosome band 11q23, suggesting that antibody 7.1 may be useful in the rapid identification of this group of poor-prognosis patients.
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Huang, Joe C., Yifan Lu, Julia Sidorova, Sylvia Chien, Vivian Oehler, Kenneth J. Kopecky i Pamela S. Becker. "Age-Related Changes in the Interaction of Acute Myeloid Leukemia with the Bone Marrow Microenvironment Correlate with Response to Treatment and Survival: A Role for L-Selectin". Blood 128, nr 22 (2.12.2016): 5063. http://dx.doi.org/10.1182/blood.v128.22.5063.5063.
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Abstract Introduction: Acute myeloid leukemia (AML) arises in the bone marrow microenvironment (BME), where cell-cell and cell-matrix adhesion promote AML survival. There is increased incidence of AML in older adults and age-related changes in the BME such as the senescence associated secretory phenotype (SASP) may promote myeloid disorders and cancer. Our objective is to further elucidate the influence of the BME on AML pathobiology. Methods: Using flow cytometry, we prospectively characterized 17 cell adhesion receptors expressed on AML blasts derived from 106 patient blood and bone marrow samples on an IRB approved protocol. For 55 patients, we correlated expression of these individual adhesion receptors with age, cytogenetics, complete remission (CR), relapse free survival (RFS) and overall survival (OS). We correlated expression of adhesion receptors with basal levels of DNA damage in AML blasts, as measured by phosphorylation of histone H2AX (γ-H2AX) by flow cytometry. mRNA microarray gene expression profiling (GEP) on 30 patients, we examined for age-associated differences in the gene expression of cell-cell and cell-matrix adhesion proteins. For 6 patients, we evaluated for changes in GEP that occur in AML blasts with adhesion to plates coated with alternative spliced fibronectin peptide CH296, RetronectinTM (RN) vs. bovine serum albumin (BSA) control. Results: We found a significant positive correlation between L-selectin cell surface expressed protein levels with advancing age (Spearman r = 0.35, p = 0.009) (Figure 1). The response to treatment (CR/CRi) rate, but not RFS, increased with greater surface expression of the following adhesion proteins: CD11a (αL), CD29 (β1), CD44, CD49a (α1) and CD49e (α5). OS improved with greater cell surface expressed protein levels of CD11a (αL) and CD29 (β1). There was a significant negative correlation in L-selectin mRNA levels with basal DNA damage in AML blasts, as measured by γ-H2AX (Spearman r = -0.6, p = 0.005). To further investigate the relationship between L-selection expression and DNA damage in AML, we cultured AML blasts on an L-selectin ligand, P-selectin glycoprotein-1 (PSGL-1) vs. BSA control. We observed increased blast survival and reduced apoptosis when adherent on PSGL-1 compared to BSA after treatment with cytarabine arabinoside (Ara-C) in 4/15 (27%) of samples tested (Figure 2). Ingenuity Pathway Analysis (IPA) results on the gene expression data showed age-associated changes in the expression of L-selectin and cell-matrix proteins involved in the SASP, such as tissue inhibitor of metalloproteinases (TIMP). Adhesion of AML blasts to RN vs. BSA control resulted in up-regulation of genes involved in protein ubiquitination and the PI3K/AKT, nuclear factor-kappa beta (NF-kβ) and IL-8 signaling pathways. Conclusions: Age-related changes in the expression of L-selectin, cell-cell and cell-matrix proteins in AML blasts appear to influence DNA damage signaling/response (DDR), promote Ara-C resistance, and influence patient response to treatment and survival. Adhesion of AML blasts to the BME results in up-regulation of cell survival pathways that confer resistance to apoptosis and maintenance of the SASP. Our results support disruption of L-selectin and other BME-mediated interactions as potential targets to enhance cytotoxicity to chemotherapy and improve age-specific outcomes in AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Becker: Invivoscribe: Honoraria; CVS Caremark: Other: Accordant Health Services Medical Advisory Board; Millennium: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding; Pfizer: Other: Scientific Steering Committee for a post marketing study; JW Pharmaceutical: Research Funding.
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Feuchtinger, Tobias, Matthias Pfeiffer, Alexander Pfaffle, Heiko-Manuel Telschik, Rupert Handgretinger, Dorothee Wernet, Michael Schumm, Ramin Lotfi i Peter Lang. "Alloreactivity of Natural Killer Cell Clones Against Childhood Precursor-B Lymphoblastic Leukemia Cells Is Determined by Differential KIR Expression." Blood 108, nr 11 (16.11.2006): 3691. http://dx.doi.org/10.1182/blood.v108.11.3691.3691.
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Abstract Relapse after allogeneic stem cell transplantation of patients with acute lymphoblastic leukemia (ALL) remains a major problem. A beneficial impact of alloreactive NK cells has been reported for myeloid malignancies, but has been questionable for B-lineage-ALL. Here we show that the majority of NK cell clones from healthy donors could effectively lyse primary blasts from a representative childhood precurser-B-ALL and demonstrate the relevance of differential surface expression of KIRs (killer cell immunglobulin like receptors CD158a, CD158b and CD158e) for antileukemic alloreactivity. More than 79% of clones exerted specific lysis >40% against primary ALL blasts. Mismatch of effector/target HLA-C type (KIR-ligand incompatibility) did not correlate with antileukemic alloreactivity, although non-malignant lymphoblastoid cell lines were lysed according to KIR-ligand incompatibility. In contrast differential surface expression of the three major KIRs showed significant impact on the antileukemic activity against precursor-B-ALL blasts. NK clones with none of the three KIRs or a single KIR that recognized no ligand, were not inhibited by the targets and exerted higher lysis (p = <0.03) in comparison to NK clones with expression of one or more KIRs with a ligand on the ALL blasts. In conclusion the differential surface expression of KIRs is relevant to predict NK cell activity against childhood lymphoid leukemia.
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Borowitz, M. J., J. J. Shuster, C. I. Civin, A. J. Carroll, A. T. Look, F. G. Behm, V. J. Land, D. J. Pullen i W. M. Crist. "Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: a Pediatric Oncology Group study." Journal of Clinical Oncology 8, nr 8 (sierpień 1990): 1389–98. http://dx.doi.org/10.1200/jco.1990.8.8.1389.
Pełny tekst źródłaStreszczenie:
We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.
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Buhring, HJ, I. Sures, B. Jallal, FU Weiss, FW Busch, WD Ludwig, R. Handgretinger, HD Waller i A. Ullrich. "The receptor tyrosine kinase p185HER2 is expressed on a subset of B- lymphoid blasts from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia". Blood 86, nr 5 (1.09.1995): 1916–23. http://dx.doi.org/10.1182/blood.v86.5.1916.bloodjournal8651916.
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The class I receptor tyrosine kinase (RTK) HER2 is an oncoprotein that is frequently involved in the pathogenesis of tumors of epithelial origin. Here we report mRNA expression in peripheral blood and bone marrow cells from healthy donors in hematopoietic cell lines and leukemic blasts from patients with acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphoblastic leukemia (CLL), and chronic myeloid leukemia (CML). However, cell surface expression of HER2 protein (p185HER2) was found exclusively on a subset of leukemic cells of the B-lymphoblastic lineage. p185HER2 expression was found on blasts in 2 of 15 samples from infants, 9 of 19 samples from adult patients with C-ALL (CD19+CD10+), and 1 of 2 samples from patients with pro-B ALL (CD19+CD10-), whereas none of the leukemic cells from patients with AML (0/30), T-ALL (0/7), CLL (0/5) (CD19+CD5+), or CML in chronic and accelerated phase (0/5) or in blast crisis with myeloid differentiation (0/14) were positive for p185HER2. However, cells from 3 of 4 patients with CML in B-lymphoid blast crisis (CD19+CD10+) expressed high levels of p185HER2, which was also found on the surface of the CML-derived B-cell lines BV-173 and Nalm-1. Our study shows p185HER2 expression on malignant cells of hematopoietic origin for the first time. Aberrant expression of this oncogenic receptor tyrosine kinase in hematopoietic cell types may be an oncogenic event contributing to the development of a subset of B- lymphoblastic leukemias.
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Demina, I. A., O. I. Illarionova1, T. Yu Verzhbitskaya, G. A. Tsaur, E. B. Rusanova, M. V. Gorchakova, E. E. Zueva i in. "Rare cases of laboratory tests discrepancies in diagnostics of pediatric Burkitt lymphoma/leukemia". Oncohematology 13, nr 3 (27.10.2018): 76–82. http://dx.doi.org/10.17650/1818-8346-2018-13-3-76-82.
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Introduction. The main features of bone marrow blasts cells in Burkitt lymphoma/leukemia (BL) are L3 morphology, mature immunophenotype of blasts with surface IgM expression, and presence of typical MYC gene rearrangements.The aim of the study was to show discrepancy examples in laboratory signs of BL.Patients and methods. 10 patients (8 boys and 2 girls) aged 1 to 18 years were included in the present study. The inclusion criterion was the identification of discrepancies between flow cytometric, morphological and cytogenetic data.Results. In 2 cases there were no rearrangements of the MYC gene. In 2 patients, the L2 morphological variant went against the presence of typical MYC gene rearrangements. In one case, undifferentiated blasts cells were described by morphology together with presence of surface IgM, and atypical genetics. In 8 patients, there was no expression of surface IgM. Of these, patients with absence of cytomorphological data cytometric and genetic data were controversial.Сonclusion. The cases presented in this study and the cases described in the literature demonstrate the importance of an attentive and comprehensive approach in evaluating the results of laboratory tests in the diagnosis of BL.
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Zhao, Xiaoxian, Wouter Korver, Shweta Singh, Eric D. Hsi i Arie Abo. "IREM-1 Is a Cell Surface Receptor Expressed in AML Blasts: Potential for Targeted Immunotherapy in AML." Blood 110, nr 11 (16.11.2007): 1792. http://dx.doi.org/10.1182/blood.v110.11.1792.1792.
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Abstract Background: Acute myeloid leukemia (AML) in adults is associated with a poor prognosis, with many patients suffering from treatment-resistant relapse. Novel targeted therapies are needed. Immune Receptor Expressed by Myeloid Cells (IREM-1), a member of the CD300L gene family, is an inhibitory receptor expressed by myeloid cells. We have generated monoclonal antibodies (mAbs) specific for IREM-1, characterized IREM-1 expression in AML blasts and explored the therapeutic potential of these antibodies in AML. Methods: mAbs were generated against the extracellular domain of IREM-1. Fresh peripheral blood or bone marrow cells from AML patients, healthy donors, or cell lines OCI-AML-2 (IREM-1+) and K562 (IREM-1−) were used for expression studies by flow cytometry (FC) with FITC-conjugated mAbs. Immunohistochemistry (IHC) was carried out on Tissue Microarrays (TMAs) of normal human tissues. mAbs were evaluated for their ability to induce lysis in Complement-dependent cytotoxicity (CDC) assays against cell lines in vitro and AML patient cells ex vivo. Results: By IHC, normal tissues lacked expression of IREM-1, with the exception of spleen and tonsil. However, using FC, expression of IREM-1 was demonstrated on monocytes, granulocytes and dendritic cells, but not on lymphocytes and platelets. FC of AML blasts showed that 18/24 (75%) cases expressed IREM-1 (range: 23.8–93.2%). The 6 negative cases of IREM-1 include 2 AML cases of inv (16) (p13q22). IREM-1 was not detectable in acute lymphocytic leukemia (ALL) blasts (n=5). CD34+ hematopoietic stem cells of control bone marrows were largely negative (n=7), only one case shown low level expression. Functionally, anti-IREM-1 antibodies mediated CDC in OCI-AML-2, while no effect was seen in IREM-1 negative K562 cells. Human embryonic kidney 293 cells only became susceptible to anti-IREM-1 antibody mediated killing after transfection with IREM-1. Furthermore, an anti-IREM-1 mAb showed dose-dependent CDC activity in all IREM-1+ AML cases tested (n=4), while no CDC activity was observed against IREM-1− AML cases (n=3) and ALL blasts (n=3). Conclusion: Our study identifies IREM-1 as a novel cell surface antigen expressed in majority of AML blasts. We have generated mAbs that are capable of mediating CDC activity against AML blasts. Currently we are testing the killing activity of anti-IREM-1 chimeric Ab and undertaking mouse xenograft model to evaluate the therapeutic impact of this target in vivo, which would offer opportunities for therapeutic intervention.
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Bonaparte, Matthew I., i Edward Barker. "Killing of human immunodeficiency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules". Blood 104, nr 7 (1.10.2004): 2087–94. http://dx.doi.org/10.1182/blood-2004-02-0696.
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Abstract In the current study, we evaluated whether the capacity of HIV to modulate major histocompatibility complex (MHC) class I molecules has an impact on the ability of autologous natural killer (NK) cells to kill the HIV-infected cells. Analysis of HIV-infected T-cell blasts revealed that the decrease in MHC class I molecules on the infected cell surface was selective. HLA-A and -B were decreased on cells infected with HIV strains that could decrease MHC class I molecules, whereas HLA-C and -E remained on the surface. Blocking the interaction between HLA-C and -E and their corresponding inhibitory receptors increased NK cell killing of T-cell blasts infected with HIV strains that reduced MHC class I molecules. Moreover, we demonstrate that NK cells lacking HLA-C and -E inhibitory receptors kill T-cell blasts infected with HIV strains that decrease MHC class I molecules. In contrast, NK cells are incapable of destroying T-cell blasts infected with HIV strains that were unable to reduce MHC class I molecules. These findings suggest that NK cells lacking inhibitory receptors to HLA-C and -E kill HIV-infected CD4+ T cells, and they indicate that the capacity of NK cells to destroy HIV-infected cells depends on the ability of the virus to modulate MHC class I molecules. (Blood. 2004;104:2087-2094)
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Winkler, Ingrid G., Valerie Barbier, Joshua Tay, Jean-Pierre Levesque, John L. Magnani, Corrine E. Fiveash i Johanna D. Erbani. "Blocking Vascular Niche E-Selectin Dampens AML Stem Cell Regeneration/Survival Potential In Vivo By Inhibiting MAPK/ERK and PI3K/AKT Signalling Pathways". Blood 134, Supplement_1 (13.11.2019): 2657. http://dx.doi.org/10.1182/blood-2019-132212.
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We have previously shown vascular E (endothelial)-selectin to play a key role in niche-mediated chemo-resistance in Acute Myeloid Leukaemia (AML). Now we report that the cell surface glycosylation of AML blasts -and thus their E-selectin-binding potential- alters during therapy and queried whether these variations influence treatment outcome. Using preclinical mouse models of 11q23-rearranged (MLL-AF9) monomyelocytic AML, we found that although AML blasts in untreated mice display a range of E-selectin-binding potentials, the blasts with highest E-selectin-binding potential dominate in bone marrow (BM) after 24hr cytarabine therapy. Indeed, the highest 10% of AML blasts for E-selectin-binding were >12-fold (p=0.0014) more likely to survive post-chemotherapy. These data raise the question whether E-selectin binding potential itself may prospectively identify AML blasts with heightened regenerative potential. An alternative explanation could be that high-binding AML blasts predominate after chemotherapy simply due to survival advantages mediated by vascular niche E-selectin interaction. To investigate this, BM AML blasts were FACs sorted from donor C57BL/6 mice based on E-selectin-binding potential (highest and lowest 10%) and transplanted into recipient mice (1,500 AML blasts/recipient, 8/gp). No significant differences in duration of disease-free survival was observed. Thus E-selectin-binding potential itself does not prognostically identify the most potent Leukemia Reconstituting Cells (LRC) that initiate relapse. To determine instead whether the AML blasts that bind E-selectin can dominate during stress because of the survival advantage of interacting with E-selectin at the niche, an identical parallel experiment was performed, the only difference being that donor mice had E-selectin blocked (GMI-1271 100mg/kg BiD) for the last 48h prior to BM harvest, FACs sort of AML blasts and recipient mouse transplant. This time we observed a significant (2-fold) extension in disease-free survival in the recipients of high-binding AMLs (from donors treated with GMI-1271) compared to all other groups (p=0.012, median disease-free survival 33 vs. 63 days). Together these data indicate that administration of E-selectin antagonists, even as a single agent, may potentially improve patient outcomes - in cases where heightened E-selectin binding potential is observed. Next we investigated the intracellular AML signaling pathways potentially dampened by E-selectin absence/blockade. Two common pathways used by malignant cells for survival/regeneration are the PI3K/AKT/mTOR/ NF-kB and RAS/MAPK/ERK pathways. We have already shown the absence (in Sele-/- mice), or therapeutic blockade of E-selectin (with GMI-1271) in mice significantly dampens PI3K/AKT/NF-kB signaling in BM AML blasts in vivo. However, AML blasts can utilize alternative pathways such as RAS/MAPK/ERK for survival signaling as well, especially in the 30% of AMLs with NRAS mutations. So we determined whether MAPK/ERK signaling in AML could be similarly altered by E-selectin absence/blockade. Indeed MAPK/ERK phosphorylation was significantly reduced (2-fold) in BM AML blasts from host mice treated 24hr with GMI-1271 and in Sele-/- hosts. Thus contact with vascular E-selectin induces a range of survival/regenerative signaling pathways within BM AML blasts that would be highly advantageous for the blast in times of stress. In summary we show, (1) vascular niche E-selectin blockade by GMI-1271 dampens malignant AML reconstitution/survival potential in vivo when administered as sole agent alone, (2) That E-selectin blockade mediates these effects via dampening a range of intracellular survival/regeneration signalling pathways in the malignant cell, and finally (3) these data suggest E-selectin blockade may synergise with other specific pathway inhibitors to improve treatment outcomes - but only for malignant cells that are appropriately glycosylated to interact with E-selectin. Disclosures Winkler: GlycoMimetics: Patents & Royalties. Levesque:GlycoMimetics: Equity Ownership. Magnani:GlycoMimetics Inc: Employment, Equity Ownership.
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Prashad, Sacha L., Leylah Drusbosky, Hassan Sibai, Mark D. Minden, Stephen J. Western, Chris Biondi, Reecha Shah i in. "Ex Vivo High-Throughput Flow Cytometry Screening Identifies Subsets of Responders to Differentiation Agents in Individual AML Patient Samples". Blood 128, nr 22 (2.12.2016): 5206. http://dx.doi.org/10.1182/blood.v128.22.5206.5206.
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Abstract Background: Prognoses for acute promyelocytic leukemia (APL) patients improved drastically upon the introduction of differentiation therapy with all-trans-retinoic acid (ATRA) in combination with conventional chemotherapy. Unfortunately, this therapeutic approach has not translated to other genetic subtypes of acute myeloid leukemia (AML) where patients demonstrate marked heterogeneity to differentiating agents. To provide improved detection of drug-induced differentiation in AML patients, we have developed a high-throughput, flow cytometry-based personalized medicine platform. Methods: Total white blood cells were isolated from each patient sample by red cell lysis, plated in serum-free media in 384-well format and incubated with drugs for 3 days. Viable cells remaining after each drug treatment were identified and quantified using cell surface marker expression, cell membrane integrity, and morphology (FSC/SSC) to determine the compound's efficacy and specificity against the blast population. Changes in cell surface marker expression and shifts in morphology indicative of blast differentiation were also evaluated with each compound. As a control for ex vivo differentiation, two APL patient samples were treated ex vivo with ATRA and we observed the blasts gaining CD66b expression indicating granulocytic differentiation. Results: A refractory AML patient was identified whose leukemic blasts exhibited a strong differentiating response to dexamethasone treatment ex vivo. This resulted in loss of CD34 expression (a marker of immature blast cells), gain of CD163 expression (a marker of monocytic/macrophage maturation) and a significant change in cellular size and granularity. After being enrolled in a clinical trial (REB: 13-6962-C) the patient was treated based on the assay for 1 week (40 mg/day) with dexamethasone. Post-treatment samples from the peripheral blood and bone marrow of the patient exhibited the same morphological and cell surface marker changes predicted by the ex vivo assay. The CD163+ cells in the patient also gained additional markers of myeloid differentiation (CD11b, CD14, CD16). After additional cytarabine and fludarabine treatment, the patient remains in remission 4 months post-treatment. Conclusions: Following this initial study, we have continued to identify subgroups of both AML and Myelodysplastic Syndrome patients where blasts differentiate in response to dexamethasone, calcitriol, ATRA or other known differentiating agents using unique cell surface markers of monocytic and myeloid maturation. Flow cytometry expression changes correlated with changes in morphology as observed by May-Grunwald Giemsa staining. In the patient described above this included an increase in cytoplasm and vacuoles consistent with monocytic/macrophage differentiation, which positively correlates with CD163 expression. We aim to apply our assay towards the identification of subgroups of AML patients who respond to differentiation therapies and develop clinical trials to combine differentiating agents with chemotherapy. This approach has the potential to extend the clinical success of APL differentiation therapy to AML patients. Disclosures Prashad: Notable Labs: Employment, Equity Ownership. Western:Notable Labs: Consultancy. Biondi:Notable Labs: Employment. Shah:Notable Labs: Employment. Liu:Notable Labs: Employment, Equity Ownership. Nguyen:Notable Labs: Employment, Equity Ownership. Warnock:Notable Labs: Employment, Equity Ownership. Quinzio:Notable Labs: Employment, Equity Ownership. De Silva:Notable Labs: Employment, Equity Ownership. Schimmer:Novartis: Honoraria. Heiser:Notable Labs: Employment, Equity Ownership.
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Hutchenson, K. D., i R. B. Herrmann. "Spectral Examination of the 16 June 1992 Earthquake and Quarry Blast Near Evansville, Indiana". Seismological Research Letters 64, nr 2 (1.04.1993): 169–84. http://dx.doi.org/10.1785/gssrl.64.2.169.
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Abstract On 16 June 1992, an mLg 2.3 earthquake occurred in southwestern Indiana, near Evansville. This area is part of the Illinois Basin coal belt, an area of active surface mines with numerous strip-mine blasts daily. The co-location of earthquakes and strip-mine blasts enable spectral comparisons without significant concern for differences due to path propagation effects. Discriminating between the two types of events can be done visually due to the distinctive appearance of the Rg phase in strip-mine blasts and high frequency coda of earthquakes. A strong Rg phase is indicative of shallow source depths. However, earthquakes previously located at shallow depths elsewhere within the Illinois Basin do not exhibit a distinctive Rg phase, indicating either poor control in focal depth determination or a fundamental difference in source mechanism. Visual and spectral examination shows that earthquakes are richer in energy at higher frequencies than strip-mine blasts. Earthquakes have significant energy at 20–30 Hz, while the significant energy content of blasts is closer to 10 Hz. The significant difference compared to previous earthquake-nuclear explosion discriminant studies is that the chemical explosion has reduced high frequency content compared to the earthquake.
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Calais, Eric, J. Bernard Minster, Michelle Hofton i Michael Hedlin. "Ionospheric signature of surface mine blasts from Global Positioning System measurements". Geophysical Journal International 132, nr 1 (27.02.2002): 191–202. http://dx.doi.org/10.1046/j.1365-246x.1998.00438.x.
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Cooper, Todd Michael, Sharyn D. Baker, Jennifer Direnzo, Tanya M. Trippett, Lia Gore, Aru Narendran, Keith J. August i in. "Chemosensitization and Mobilization Of AML/ALL/MDS With Plerixafor (AMD 3100), a CXCR4 Antagonist: A Phase I Study Of Plerixafor + Cytarabine and Etoposide In Pediatric Patients With Acute Leukemia and MDS". Blood 122, nr 21 (15.11.2013): 2680. http://dx.doi.org/10.1182/blood.v122.21.2680.2680.
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Abstract Background The protection afforded to leukemic blasts by the bone marrow microenvironment has been identified as an important mechanism of chemoresistance. Interaction between stroma-derived growth factor-1 alpha (SDF-1α) and its receptor, CXC chemoreceptor 4 (CXCR4) are implicated in chemotaxis, homing, and survival/apoptosis of normal and malignant hematopoietic cells in the bone marrow. Preclinical data demonstrates that plerixafor (AMD3100), a CXCR4 antagonist, disrupts tumor-stroma interactions and mobilizes leukemia cells from their protective stromal environment. Combinations of CXCR4 antagonists with chemotherapy have demonstrated preclinical synergy. Chemosensitization using plerixafor prior to cytotoxic chemotherapy has been tested in adults with acute leukemia. We report the first Phase I study of plerixafor (NCT01319864) delivered prior to chemotherapy in children with relapsed/refractory acute leukemia and MDS. Study Design Patients > 3 and < 30 years of age with relapsed or refractory AML, ALL, MDS or mixed phenotype acute leukemia were eligible for enrollment. Plerixafor was administered intravenously (IV) once daily followed 4 hours later by cytarabine (1 gm/m2 every 12 hours) and IV etoposide (150 mg/m2 daily) for a total of 5 days of therapy. Plerixafor pharmacokinetic studies were performed on days 1 and 5. Correlative biology studies included measurement of peripheral blood mobilization of leukemic blasts by flow cytometry, quantitative expression of CXCR4 on leukemic blasts, and the change in surface expression of CXCR4 on residual blasts after course 1 of therapy. Results Eighteen evaluable patients (11 AML, 6 ALL, 1 MDS) were treated at 4 dose levels of plerixafor (6, 9, 12, and 15 mg/m2/dose) utilizing a Rolling 6 design. The median number of prior regimens was 2.8 (range 1-7) for ALL and 2.1 (range 1-4) for AML. Six patients had high risk cytogenetics (3 ALL, 2 AML, 1 MDS). Three patients with ALL and 4 with AML had prior hematopoietic stem cell transplant (HSCT). Toxicities were consistent with intensive relapsed leukemia regimens. The most common Grade 1 and 2 toxicities attributed to plerixafor occurring in >10% of patients were anorexia, nausea, vomiting, diarrhea, fatigue, and dizziness. There were no dose limiting toxicities and no delay in count recovery attributable to plerixafor. There were responses in 3 (2 complete response (CR), 1 complete response with incomplete hematologic recovery (CRi)) of 11 AML patients (27%) and no responses in those with ALL or MDS. Peripheral leukemia-specific blast counts (measured by flow cytometry before and 4 hours after the first dose of plerixafor) demonstrated mobilization of leukemic blasts in 14 of 16 patients with samples available, with median fold increase of 3.4 (range 1.3 to 17). The degree of leukemic blast mobilization correlated positively with quantitative leukemia blast surface CXCR4 protein expression (expressed as median fluorescence index relative to isotype control), with a Pearson’s correlation co-efficient of 0.56, p=0.02. Mean ± SD plerixafor AUC values at 12 and 15 mg/m2 were 5074 ± 380 and 5732 ± 573 ng*h/mL, respectively. Drug clearance was similar between days 1 and 5 (p=0.195). Conclusion The favorable safety profile of plerixafor and biologic rationale demonstrated in this clinical trial support further clinical study of chemosensitization using CXCR4 antagonists in overcoming chemoresistance. Disclosures: Off Label Use: Plerixafor is not approved for chemosensitization in the treatment of acute leukemia.
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Mirro, J., GR Antoun, TF Zipf, S. Melvin i S. Stass. "The E rosette-associated antigen of T cells can be identified on blasts from patients with acute myeloblastic leukemia". Blood 65, nr 2 (1.02.1985): 363–67. http://dx.doi.org/10.1182/blood.v65.2.363.363.
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Abstract Monoclonal antibody T-11, considered specific for the sheep erythrocyte rosette-associated antigen of T cells, reacted with leukemic blasts from four of 23 patients with morphologic and cytochemical criteria for acute myeloblastic leukemia (AML). Although 83%, 87%, 88%, and 96% of the blasts from these patients reacted with T-11, only one patient demonstrated a small percentage of heat-stable E rosettes (5%). Antibody 9.6, which also reacts with the E rosette-associated antigen, was tested on blasts from two of the T-11-positive patients and was also strongly reactive (96% and 98%). Dual staining of blasts from these two patients demonstrated a small number of cells that simultaneously expressed the E rosette-associated antigen and myeloid- associated cytochemistries (myeloperoxidase [MPO] and Sudan black B). Additionally, leukemic blasts were identified that simultaneously expressed the E rosette-associated antigen and contained Auer rods. Antibody OKT-11 immunoprecipitated a 48,100-dalton glycoprotein from these leukemic blasts that is similar in molecular weight to that previously determined for the T cell surface protein (Tp50), thus providing strong evidence that this molecule can be found in some cases of AML. Because cells simultaneously expressing both the E rosette- associated antigen and MPO were identified, it would appear likely that leukemic blasts with only the E rosette-associated antigen or only MPO arose from the same progenitor. Our findings further demonstrate that the epitopes identified by antibodies OKT-11, T-11, and 9.6 are not always associated with, or sufficient for, 37 degrees C E rosette formation and can be found on blasts from patients with AML.
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Mirro, J., GR Antoun, TF Zipf, S. Melvin i S. Stass. "The E rosette-associated antigen of T cells can be identified on blasts from patients with acute myeloblastic leukemia". Blood 65, nr 2 (1.02.1985): 363–67. http://dx.doi.org/10.1182/blood.v65.2.363.bloodjournal652363.
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Monoclonal antibody T-11, considered specific for the sheep erythrocyte rosette-associated antigen of T cells, reacted with leukemic blasts from four of 23 patients with morphologic and cytochemical criteria for acute myeloblastic leukemia (AML). Although 83%, 87%, 88%, and 96% of the blasts from these patients reacted with T-11, only one patient demonstrated a small percentage of heat-stable E rosettes (5%). Antibody 9.6, which also reacts with the E rosette-associated antigen, was tested on blasts from two of the T-11-positive patients and was also strongly reactive (96% and 98%). Dual staining of blasts from these two patients demonstrated a small number of cells that simultaneously expressed the E rosette-associated antigen and myeloid- associated cytochemistries (myeloperoxidase [MPO] and Sudan black B). Additionally, leukemic blasts were identified that simultaneously expressed the E rosette-associated antigen and contained Auer rods. Antibody OKT-11 immunoprecipitated a 48,100-dalton glycoprotein from these leukemic blasts that is similar in molecular weight to that previously determined for the T cell surface protein (Tp50), thus providing strong evidence that this molecule can be found in some cases of AML. Because cells simultaneously expressing both the E rosette- associated antigen and MPO were identified, it would appear likely that leukemic blasts with only the E rosette-associated antigen or only MPO arose from the same progenitor. Our findings further demonstrate that the epitopes identified by antibodies OKT-11, T-11, and 9.6 are not always associated with, or sufficient for, 37 degrees C E rosette formation and can be found on blasts from patients with AML.
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Zhang, Yanyan, Dima Jouni, Monika Wittner, Hakim Bouamar, Herve Dombret, Paul Coppo, Paule Opolon i in. "CXCR4 Blockade as a New Targeted Therapy for Acute Myeloide Leukemia Characterised by High Cell Surface Density of CXCR4." Blood 114, nr 22 (20.11.2009): 4570. http://dx.doi.org/10.1182/blood.v114.22.4570.4570.
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Abstract Abstract 4570 Stromal cell-derived factor 1 (SDF-1)/CXCR4 axis plays key roles in hematopoiesis regulating the interactions between hematopoietic cells and their stromal microenvironment within the bone marrow, their trafficking from the bone marrow to blood, their proliferation and survival. SDF-1/CXCR4 interactions also participate in the development of leukemic blasts in acute myeloid leukaemia (AML) influencing their trafficking, survival and differentiation. We used the xenotransplantation model of nonobese diabetes/severe combined immunodeficiency γcnull (NOG) mice reconstituted with human primary cells from AML patients and 2 small molecule competitive antagonists of CXCR4, AMD3100 and TN140 to better define the role of CXCR4/SDF-1 on the leukemic blast burden within the bone marrow and in extramedullary sites. In a first set of experiments, we investigated whether there was a correlation between CXCR4 expression or function on leukemic blasts and their ability to engraft the bone marrow of NOG mice in 34 patients. Using flow cytometric analyses, we observed that CXCR4 membrane expression was highly variable between patients. This expression did not correlate with engraftment. In addition, SDF-1 responsiveness evaluated by transwell migration only marginally correlated with engraftment. However, in these initial analyses, we observed that the differences between engrafters and nonengrafters were significant if the cut-point migration is set to 20%. Patients with higher chemotactic response to SDF-1 had a significantly increased NOG repopulating ability. In further studies, NOG mice reconstituted with AML cells from 5 different patients were treated with optimal concentration of either AMD3100 or TN140 for 1 week. We observed that CXCR4 inhibition by TN140 (used as a single therapy) had profound inhibitory effects on the proliferation and the development of extramedullary dissemination of the disease in this xenotransplantation. This patient had FAB M1 leukemia and initially exhibits high CXCR4 level on blast. Our study demonstrated that CXCR4 inhibition in selected patients might be a potent therapy against leukemic development. Disclosures: Bouamar: Association pour la Recherche sur le Cancer: Employment; Cancéropôle IDF: Employment.