scholarly journals Nonhuman primates express human leukemia-associated antigens

Blood ◽  
1984 ◽  
Vol 64 (5) ◽  
pp. 1074-1078
Author(s):  
JM Pesando ◽  
TA Conrad
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Nonhuman Primates ◽  
Lymphoblastic Leukemia ◽  
Adherent Cell ◽  
Human Leukemia ◽  
Papio Cynocephalus ◽  
Normal Tissues ◽  
Leukemia Antigen

Serologic studies using four murine monoclonal antibodies specific for the common acute lymphoblastic leukemia antigen (CALLA) and five monoclonal antibodies specific for the gp24 surface antigen indicate that these leukemia-associated antigens are present on cells of comparable tissues in man and in four nonhuman primates. As in man, adherent cell populations obtained from skin, lung, and bone marrow of Macaca fascicularis, M mulatta, M nemestrina, and Papio cynocephalus react with these antibodies. Similarly, granulocytes from both man and these nonhuman primates bind CALLA- and gp24-specific antibodies. Radioimmune precipitation experiments confirm the identity of these antigens. Our studies suggest that nonhuman primates can be used to screen serologic reagents to leukemia-associated antigens for potential toxic effects on normal tissues prior to their use in man. Similarly, nonhuman primates could be employed to assess the possible role of antigen-positive stromal cells in the reconstitution of bone marrow following transplantation.

scholarly journals Nonhuman primates express human leukemia-associated antigens

Blood ◽  
1984 ◽  
Vol 64 (5) ◽  
pp. 1074-1078 ◽  
Author(s):  
JM Pesando ◽  
TA Conrad
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Nonhuman Primates ◽  
Lymphoblastic Leukemia ◽  
Adherent Cell ◽  
Human Leukemia ◽  
Papio Cynocephalus ◽  
Normal Tissues ◽  
Leukemia Antigen

Abstract Serologic studies using four murine monoclonal antibodies specific for the common acute lymphoblastic leukemia antigen (CALLA) and five monoclonal antibodies specific for the gp24 surface antigen indicate that these leukemia-associated antigens are present on cells of comparable tissues in man and in four nonhuman primates. As in man, adherent cell populations obtained from skin, lung, and bone marrow of Macaca fascicularis, M mulatta, M nemestrina, and Papio cynocephalus react with these antibodies. Similarly, granulocytes from both man and these nonhuman primates bind CALLA- and gp24-specific antibodies. Radioimmune precipitation experiments confirm the identity of these antigens. Our studies suggest that nonhuman primates can be used to screen serologic reagents to leukemia-associated antigens for potential toxic effects on normal tissues prior to their use in man. Similarly, nonhuman primates could be employed to assess the possible role of antigen-positive stromal cells in the reconstitution of bone marrow following transplantation.

scholarly journals Expression of the three myeloid cell-associated immunoglobulin G Fc receptors defined by murine monoclonal antibodies on normal bone marrow and acute leukemia cells

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1951-1956
Author(s):  
ED Ball ◽  
J McDermott ◽  
JD Griffin ◽  
FR Davey ◽  
R Davis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Acute Leukemia ◽  
Cell Sorting ◽  
Lymphoblastic Leukemia ◽  
Mononuclear Phagocytes ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Normal Bone Marrow ◽  
Normal Bone

Monoclonal antibodies (MoAbs) have been prepared recently that recognize the three cell-surface receptors for the Fc portion of immunoglobulin (Ig), termed Fc gamma RI (MoAb 32.2), Fc gamma R II (MoAb IV-3), and Fc gamma R III (MoAb 3G8) that are expressed on selected subsets of non-T lymphocyte peripheral blood leukocytes. In the blood, Fc gamma R I is expressed exclusively on monocytes and macrophages, Fc gamma R II on granulocytes, mononuclear phagocytes, platelets, and B cells, and Fc gamma R III on granulocytes and natural killer (NK) cells. We have examined the expression of these molecules on normal bone marrow (BM) cells and on leukemia cells from the blood and/or BM in order to determine their normal ontogeny as well as their distribution on leukemic cells. BM was obtained from six normal volunteers and from 170 patients with newly diagnosed acute leukemia. Normal BM cells were found to express Fc gamma R I, II, and III with the following percentages: 40%, 58%, and 56%, respectively. Cell sorting revealed that both Fc gamma R I and Fc gamma R II were detectable on all subclasses of myeloid precursors as early as myeloblasts. Cell sorting experiments revealed that 66% of the granulocyte-monocyte colony-forming cells (CFU-GM) and 50% of erythroid burst-forming units (BFU-E) were Fc gamma R II positive with only 20% and 28%, respectively, of CFU-GM and BFU-E were Fc gamma R I positive. Acute myeloid leukemia (AML) cells expressed the three receptors with the following frequency (n = 146): Fc gamma R I, 58%; Fc gamma R II, 67%; and Fc gamma R III, 26% of patients. Despite the fact that Fc gamma R I is only expressed on monocytes among blood cells, AML cells without monocytoid differentiation (French-American-British [FAB]M1, M2, M3, M6) were sometimes positive for this receptor. However, Fc gamma R I was highly correlated with FAB M4 and M5 morphology (P less than .001). Fc gamma R II was also correlated with FAB M4 and M5 morphology (P = .003). Cells from 11 patients with acute lymphoblastic leukemia were negative for Fc gamma R I, but six cases were positive for Fc gamma R II and III (not the same patients). These studies demonstrate that Ig Fc gamma R are acquired during normal differentiation in the BM at or before the level of colony-forming units. In addition, we show that acute leukemia cells commonly express Fc gamma R.

scholarly journals CALLA-positive myeloma: an aggressive subtype with poor survival

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 229-232
Author(s):  
BG Durie ◽  
TM Grogan
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Median Survival ◽  
Lymphoblastic Leukemia ◽  
Myeloma Cell ◽  
Negative Group ◽  
Poor Survival ◽  
Aggressive Subtype ◽  
Leukemia Antigen

Detailed immunotyping was carried out on 21 direct myeloma bone marrow aspirates and eight human myeloma cell lines. Four previously untreated common acute lymphoblastic leukemia antigen (CALLA)-positive myeloma patients were identified and six of eight cell lines (75%) were also positive. CALLA positivity, as part of an immature B phenotype, was found to correlate with very aggressive clinical disease: median survival six months v 56 months for the CALLA-negative group.

scholarly journals Blood kinetics, tissue distribution, and radioimaging of anti-common chronic lymphatic leukemia antigen (cCLLa) monoclonal antibody CLL2 in mice transplanted with cCLLa-bearing human leukemia cells

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1853-1861 ◽  
Author(s):  
GB Faguet ◽  
JF Agee ◽  
JT DiPiro
Keyword(s):  
Monoclonal Antibody ◽  
Specific Activity ◽  
Human Leukemia ◽  
Chronic Lymphatic Leukemia ◽  
Prolymphocytic Leukemia ◽  
Normal Tissues ◽  
Lymphatic Leukemia ◽  
Human Leukemia Cells ◽  
Glycoprotein Antigen ◽  
Leukemia Antigen

Abstract The blood kinetics and biodistribution of anti-common chronic lymphatic leukemia antigen (cCLLa) monoclonal antibody (MoAb) CLL2 were assessed in mice bearing cCLLa+ tumors. The cCLLa is a 69-Kd glycoprotein antigen expressed selectively by malignant B cells in human CLL, hairy cell leukemia (HCL), and prolymphocytic leukemia. Immunoreactive 125I- CLL2 (5 micrograms/mouse, specific activity 4.3 microCi/micrograms) was injected intravenously in mice bearing HCL-derived EH xenografts, and blood kinetics and biodistribution were ascertained up to 16 days postinjection. Radioimages were also obtained up to 72 hours after injecting 10 micrograms/mouse (specific activity 50.1 microCi/micrograms) of 125I-CLL2. Distinct 125I-CLL2 blood kinetics were observed in EH engrafted compared with tumor-free mice including: a longer 125I-CLL2 T 1/2 (153 hours v 72 hours), and a considerably greater blood clearance (173 mg/h v 54.7 mg/h) with biexponential rather than monoexponential configuration; and a greater volume of antibody distribution (31,483 mg v 5,729 mg). These data suggest more rapid tissue uptake by grafted tumours. Preferential 125I-CLL2 uptake by EH tumours relative to normal tissues was observed beginning 24 hours postinjection (mean ratio, 4.2) with average peak tumor 125I-CLL2 levels of 428.7 pg/mg. 125I-CLL2 uptake selectivity by EH tumor cells was also supported by: (1) negligible 125I-CLL2 uptake by cCLLa- Molt-4 xenografts (average 29.1 pg/mg 24 hours postinjection); (2) background uptake of cCLLa-irrelevant MoAb 131I-LEU1 by CD5- EH xenografts (average 31.4 pg/mg 48 hours postinjection); and (3) by scintigraphy. The EH xenograft mouse model might be useful to ascertain preclinically the anti-tumor effect of anti-cCLLa MoAbs and of their conjugated derivatives.

scholarly journals Expression of the three myeloid cell-associated immunoglobulin G Fc receptors defined by murine monoclonal antibodies on normal bone marrow and acute leukemia cells

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1951-1956 ◽  
Author(s):  
ED Ball ◽  
J McDermott ◽  
JD Griffin ◽  
FR Davey ◽  
R Davis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Acute Leukemia ◽  
Cell Sorting ◽  
Lymphoblastic Leukemia ◽  
Mononuclear Phagocytes ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Normal Bone Marrow ◽  
Normal Bone

Abstract Monoclonal antibodies (MoAbs) have been prepared recently that recognize the three cell-surface receptors for the Fc portion of immunoglobulin (Ig), termed Fc gamma RI (MoAb 32.2), Fc gamma R II (MoAb IV-3), and Fc gamma R III (MoAb 3G8) that are expressed on selected subsets of non-T lymphocyte peripheral blood leukocytes. In the blood, Fc gamma R I is expressed exclusively on monocytes and macrophages, Fc gamma R II on granulocytes, mononuclear phagocytes, platelets, and B cells, and Fc gamma R III on granulocytes and natural killer (NK) cells. We have examined the expression of these molecules on normal bone marrow (BM) cells and on leukemia cells from the blood and/or BM in order to determine their normal ontogeny as well as their distribution on leukemic cells. BM was obtained from six normal volunteers and from 170 patients with newly diagnosed acute leukemia. Normal BM cells were found to express Fc gamma R I, II, and III with the following percentages: 40%, 58%, and 56%, respectively. Cell sorting revealed that both Fc gamma R I and Fc gamma R II were detectable on all subclasses of myeloid precursors as early as myeloblasts. Cell sorting experiments revealed that 66% of the granulocyte-monocyte colony-forming cells (CFU-GM) and 50% of erythroid burst-forming units (BFU-E) were Fc gamma R II positive with only 20% and 28%, respectively, of CFU-GM and BFU-E were Fc gamma R I positive. Acute myeloid leukemia (AML) cells expressed the three receptors with the following frequency (n = 146): Fc gamma R I, 58%; Fc gamma R II, 67%; and Fc gamma R III, 26% of patients. Despite the fact that Fc gamma R I is only expressed on monocytes among blood cells, AML cells without monocytoid differentiation (French-American-British [FAB]M1, M2, M3, M6) were sometimes positive for this receptor. However, Fc gamma R I was highly correlated with FAB M4 and M5 morphology (P less than .001). Fc gamma R II was also correlated with FAB M4 and M5 morphology (P = .003). Cells from 11 patients with acute lymphoblastic leukemia were negative for Fc gamma R I, but six cases were positive for Fc gamma R II and III (not the same patients). These studies demonstrate that Ig Fc gamma R are acquired during normal differentiation in the BM at or before the level of colony-forming units. In addition, we show that acute leukemia cells commonly express Fc gamma R.

scholarly journals Myelomonocytic antigen positive multiple myeloma

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 763-769 ◽  
Author(s):  
TM Grogan ◽  
BG Durie ◽  
CM Spier ◽  
L Richter ◽  
E Vela
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Antigen Expression ◽  
Survival Duration ◽  
Double Labelling ◽  
Myeloma Cells ◽  
Myeloid Antigens ◽  
A Cell ◽  
Multilineage Potential ◽  
Leukemia Antigen

Abstract In a four year span, between 1983 and 1987, 215 bone marrow and cell culture samples from 125 myeloma patients were immunotyped and coexpression of myelomonocytic and plasma cell antigens occurred in 16 (13%). We employed both immunohistochemical and flow cytometry methods including coplots and double labelling. Three types of myeloma cases were found: (1) those with isolated myeloid antigen coexpression, usually Leu M1 or esterase (BE, CE) positive (11 cases); (2) those with multiple myeloid antigens (Leu M1, M3, M5, MY7, BE, CE) (four cases); and (3) one case beginning as 1 and ending as 2. Isolated myeloid antigen expression was generally associated with typical features of myeloma with survival close to the anticipated median (33 months), while multiple myeloid antigen expression was associated with more aggressive disease and shorter survival duration (median survival 16 months). The latter subgroup also had other poor prognostic factors including high labelling index and common acute lymphoblastic leukemia antigen (CALLA) positivity. Other features found overall were frequent abnormal karyotypes (seven of 12 abnormal) and coexpressed IgA (eight of 16); all IgA+ cases also coexpressed Leu M1. We conclude that there is an unusual and unexpected predilection for coexpression of myelomonocytic antigens in myeloma cells. The reasons are not immediately obvious. Whether the coexpression indicates that myeloma cells truly have latent multilineage potential or just aberrantly coexpress other hematopoietic antigens as a manifestation of malignancy remains to be explained. However, a cell line established from the bone marrow of one patient is a valuable scientific tool allowing detailed analysis of these questions.

The Role of Microrna-196a-1 and Microrna-196b in Acute T-Lymphoblastic Leukemia and Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1607-1607
Author(s):  
Ebru Coskun ◽  
Eva Kristin von der Heide ◽  
Cornelia Schlee ◽  
Nicola Goekbuget ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymphoblastic Leukemia ◽  
Mirna Precursor ◽  
Acute Leukemias ◽  
Aberrant Expression ◽  
Gm Csf ◽  
Fold Reduction ◽  
Precursor Molecules

Abstract Abstract 1607 Poster Board I-633 INTRODUCTION Overexpression of the gene ERG (v-ets erythroblastosis virus E26 oncogene homolog) is an adverse prognostic factor in adult patients with acute T-lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). However, the underlying biology remains unknown. The aim of this study was to investigate the regulation of ERG expression by microRNAs (miRNAs) and to explore their potential role in acute leukemia and normal hematopoiesis. METHODS: A bioinformatic database search was carried out using the Targetscan, Pictar, and Human microRNA target tools to predict ERG regulating miRNAs. Verification of ERG as potential target of predicted miRNAs was performed by AMAXA transfection of miRNA precursor molecules in the myeloid leukemic cell line KG1a. After 24 hours (hrs) and 48 hrs total RNA was extracted using the Trizol reagent. Overexpression of the miRNAs was confirmed by TaqMan MicroRNA assays and ERG expression was determined by real-time RT-PCR. Moreover, specific binding of miRNAs to the 3'UTR of ERG was verified by luciferase reporter assays co-transfecting the ERG 3'UTR cloned into the psiCHECK-2 luciferase vector with miRNA precursor molecules. To investigate the expression of miRNAs during hematopoietic maturation, CD34 positive bone marrow cells from healthy individuals were in vitro cultured using the cytokines SCF and IL-3 (maintenance culture) with the addition of EPO or G-/GM-CSF. Cells were harvested after 3, 6, 9, 13, 16, and 20 days and miRNA expression levels were measured. The expression of miR-196a-1 and miR-196b was also studied in acute leukemias including bone marrow samples of adult patients with newly diagnosed T-ALL (n=105) and AML (n=34). RESULTS: By the database search, a total of 13 miRNAs were predicted to potentially regulate ERG and were further studied. Of these, only the miRNAs miR-196a-1 and miR-196b induced a significant reduction of ERG expression levels. After 24 hrs ERG was significantly down-regulated by 36% (after miR-196a-1 transfection) and by 42% (after miR-196b transfection) as well as after 48 hrs by 43% (after miR-196a-1 transfection) and by 47% (after miR-196b transfection) compared to the controls. The luciferase assays revealed a 30% and 40% luciferase activity reduction in miR-196a-1 and miR-196b transfected cells, respectively, compared to the miRNA-missense transfected cells. This confirmed the direct binding of these miRNAs to the ERG 3'UTR. During hematopoietic differentiation of normal CD34 positive progenitors, expression of miR-196a-1 was constant over time using the different cytokine conditions. In contrast, the expression of miR-196b decreased substantially during the in vitro differentiation (maintenance culture: 20-fold reduction; EPO: 18-fold reduction; G-/GM-CSF: 13-fold reduction - from day 0 to day 9). In acute leukemia, we found that miR-196a-1 was significantly higher expressed in AML compared to bone marrow samples of healthy donors (P=0.02). In T-ALL, miR-196a-1 was significantly up-regulated in patients with aberrant expression of myeloid markers (P=0.04), and miR-196b expression correlated with CD34 expression (P=0.003). In contrast to the reported adverse prognostic impact of ERG, expression of these miRNAs had no prognostic significance in T-ALL. CONCLUSION: This study identifies miR196a-1 and miR-196b as ERG regulators. We show that miR-196b is specifically down-regulated during hematopoietic differentiation, thus indicating a specific role of this miRNA in hematopoiesis. Moreover, the aberrant expression of miR-196a-1 and miR-196b in T-ALL and AML points to a potential role of these miRNAs in acute leukemias. Disclosures No relevant conflicts of interest to declare.

Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2321-2321
Author(s):  
Sebastian Giebel ◽  
Beata Stella-Holowiecka ◽  
Malgorzata Krawczyk-Kulis ◽  
Nicola Goekbuget ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Minimal Residual

Abstract Abstract 2321 Poster Board II-298 The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT. Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases. With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009). CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL. Disclosures: No relevant conflicts of interest to declare.

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