Heterogeneity in the specific activity and methotrexate sensitivity of dihydrofolate reductase from blast cells of acute myelogenous leukemia patients.

1985 ◽  
Vol 3 (11) ◽  
pp. 1545-1552 ◽  
Author(s):  
S Dedhar ◽  
D Hartley ◽  
D Fitz-Gibbons ◽  
G Phillips ◽  
J H Goldie
Keyword(s):  
Dihydrofolate Reductase ◽  
Acute Myelogenous Leukemia ◽  
Specific Activity ◽  
Reductase Activity ◽  
Myelogenous Leukemia ◽  
Mechanisms Of Resistance ◽  
Clinical Resistance ◽  
Dihydrofolate Reductases ◽  
Acute Myelogenous ◽  
Blast Cells

Dihydrofolate reductase activity was found to be highly heterogeneous in terms of its specific activity and methotrexate sensitivity in the blast cells of patients with acute myelogenous leukemia. None of the patients had previously been treated with methotrexate (MTX). The blast cells of four of 12 patients studied contained methotrexate-insensitive forms of dihydrofolate reductase, and the blast cells of three (distinct from the four mentioned previously) of the 12 had significantly higher dihydrofolate reductase activities than the rest. The presence of MTX-insensitive dihydrofolate reductases and high levels of enzyme activity represent intrinsic mechanisms of resistance and may explain the apparent clinical resistance of acute myelogenous leukemia to methotrexate.

scholarly journals Autologous leukemia-specific T-cell-mediated lymphocytotoxicity in patients with acute myelogenous leukemia.

1978 ◽  
Vol 147 (3) ◽  
pp. 912-922 ◽  
Author(s):  
S K Lee ◽  
R T Oliver
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Blast Cell ◽  
Third Party ◽  
Myelogenous Leukemia ◽  
Target Antigen ◽  
Leukemic Blast ◽  
Crossover Studies ◽  
Acute Myelogenous ◽  
Blast Cells ◽  
Short Term Culture

Short-term culture of acute myelogenous leukemia patient's remission lymphocytes with inactivated autologous leukemic blast cells plus allogeneic lymphocytes, generated effector T lymphocytes which were cytotoxic for the specific autologous blast cell in 11 of 14 patients studied. Experiments using Daudi and Molt 4 lymphoblastoid cell lines as third-party helper cell suggest that an HLA D locus incompatability is necessary to provide effective help in this system. Cold target inhibition experiments, crossover studies between pairs of patients, and experiments with allogeneic leukemic blast cells as priming stimulus suggest that the target antigen is only present on the specific autologous blast cell.

scholarly journals Mutation of the p53 gene in human acute myelogenous leukemia

Blood ◽  
1991 ◽  
Vol 77 (7) ◽  
pp. 1500-1507 ◽  
Author(s):  
JM Slingerland ◽  
MD Minden ◽  
S Benchimol
Keyword(s):  
Acute Myelogenous Leukemia ◽  
P53 Protein ◽  
Point Mutations ◽  
P53 Gene ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
P53 Expression ◽  
Coding Sequence ◽  
Acute Myelogenous ◽  
Blast Cells

Abstract Heterogeneity of p53 protein expression is seen in blast cells of patients with acute myelogenous leukemia (AML). p53 protein is detected in the blasts of certain AML patients but not in others. We have identified p53 protein variants with abnormal mobility on gel electrophoresis and/or prolonged half-life (t 1/2). We have sequenced the p53 coding sequence from primary blast cells of five AML patients and from the AML cell line (OCIM2). In OCIM2, a point mutation in codon 274 was identified that changes a valine residue to aspartic acid. A wild type p53 allele was not detected in these cells. Two point mutations (codon 135, cysteine to serine; codon 246, methionine to valine) were identified in cDNA from blasts of one AML patient. Both mutations were present in blast colonies grown from single blast progenitor cells, indicating that individual leukemia cells had sustained mutation of both p53 alleles. The cDNAs sequenced from blast samples of four other patients, including one with prolonged p53 protein t 1/2 and one with no detectable p53 protein, were fully wild type. Thus, the heterogeneity of p53 expression cannot be explained in all cases by genetic change in the p53 coding sequence. The prolonged t 1/2 of p53 protein seen in some AML blasts may therefore reflect changes not inherent to p53. A model is proposed in which mutational inactivation of p53, although not required for the evolution of neoplasia, would confer a selective advantage, favoring clonal outgrowth during disease progression.

Gemtuzumab ozogamicin for treatment of relapsing/refractory acute myelogenous leukemia (AML)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 16531-16531
Author(s):  
D. C. Case ◽  
M. A. Boyd ◽  
J. A. Hedlund ◽  
T. J. Ervin
Keyword(s):  
Complete Remission ◽  
Acute Myelogenous Leukemia ◽  
Single Agent ◽  
Liver Function Tests ◽  
Initial Therapy ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Blast Cells ◽  
Age Range

16531 Background: Gemtuzumab ozogamicin is a calicheamicin-conjugated anti-CD 33 monoclonal antibody studied and utilized in relapsed and refractory acute myelogenous leukemia. Methods: At our center we treated a series of refractory patients (<60 years old) and relapsed patients (>60 years old) with gemtuzumab ozogamicin over a 3 year period. We treated 20 patients: 14 males and 6 females with an age range of 21 to 77 years (median 64 years). Seven patients were refractory to multiple regimens (<60 years old) and 13 were relapsing from initial therapy (>60 years old). Cytogenetic analysis revealed 60% were intermediate-risk and 40% were poor-risk. The goal of therapy was complete remission (≤ 5% leukemia blast cells in the marrow. ≥ 9 g/dl hemoglobin, ≥1500/ul absolute neutrophil count, and platelet count ≥100,000/ul). Patients received gemtuzumab ozogamicin 9 mg/m2 I.V. days 1 and 5. All patients received at least one dose. Patients achieving complete remission were eligible to receive monthly doses of gemtuzumab ozogamicin after complete remission was obtained. Results: Of the 7 refractory patients (<60 years old), there were no complete remissions. Of 13 relapsing patients (>60 years old) there were 2 complete remissions. One patient was 64 and the other 67 years old. Both remissions lasted 2 months. All patients were treated in the hospital. Chills/fever with treatment occurred in 40% of patients. Fever/neutropenia was universal. Thirty percent had elevation of liver function tests. Conclusions: Gemtuzumab ozogamicin as a single agent is capable of producing complete remission in a small number of relapsing patients >60 years old. Remissions are short. No significant financial relationships to disclose.

scholarly journals Acidic isoferritins (leukemia-associated inhibitory activity) fail to inhibit blast proliferation in acute myelogenous leukemia

Blood ◽  
1981 ◽  
Vol 58 (3) ◽  
pp. 653-657 ◽  
Author(s):  
R Taetle
Keyword(s):  
Inhibitory Activity ◽  
Acute Myelogenous Leukemia ◽  
Blood Cells ◽  
Leukemia Cell ◽  
S Phase ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Acute Myelogenous ◽  
Blast Cells ◽  
Leukemic Clone

Abstract Cell-free extracts of bone marrow and blood cells from patients with leukemia contain an inhibitor of normal granulocyte/macrophage progenitor (CFU-GM) proliferation (leukemia-associated inhibitory activity, LIA) identified as acidic isoferritins. A comparison was made of the action of crude LIA prepared from frozen-thawed leukemic blood cells and purified spleen ferritin from a patient with chronic myelogenous leukemia, on the proliferation of blast progenitors from patients with acute myelogenous leukemia (AML), and on the promyelocytic leukemia cell line, HL-60. Crude LIA showed no inhibition of blast progenitor or HL-60 proliferation at low concentrations, but inhibited the proliferation of CFU-GM. At higher concentrations, crude LIA inhibited both blast cells and CFU-GM. Purified spleen ferritin failed to inhibit blast progenitors or HL-60 cells at any concentration tested, but inhibited both 70-day and 14-day CFU-GM. Using the thymidine “suicide„ technique, the action of LIA was confirmed as being on CFU-GM in S-phase, but it failed to affect the proliferation of blast cell in S-phase. It is concluded that acidic isoferritins inhibit normal CFU-GM but not blast cells from patients with AML. Acidic isoferritins could confer a proliferative advantage of the leukemic clone over its normal counterparts.

scholarly journals Acidic isoferritins (leukemia-associated inhibitory activity) fail to inhibit blast proliferation in acute myelogenous leukemia

Blood ◽  
1981 ◽  
Vol 58 (3) ◽  
pp. 653-657
Author(s):  
R Taetle
Keyword(s):  
Inhibitory Activity ◽  
Acute Myelogenous Leukemia ◽  
Blood Cells ◽  
Leukemia Cell ◽  
S Phase ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Acute Myelogenous ◽  
Blast Cells ◽  
Leukemic Clone

Cell-free extracts of bone marrow and blood cells from patients with leukemia contain an inhibitor of normal granulocyte/macrophage progenitor (CFU-GM) proliferation (leukemia-associated inhibitory activity, LIA) identified as acidic isoferritins. A comparison was made of the action of crude LIA prepared from frozen-thawed leukemic blood cells and purified spleen ferritin from a patient with chronic myelogenous leukemia, on the proliferation of blast progenitors from patients with acute myelogenous leukemia (AML), and on the promyelocytic leukemia cell line, HL-60. Crude LIA showed no inhibition of blast progenitor or HL-60 proliferation at low concentrations, but inhibited the proliferation of CFU-GM. At higher concentrations, crude LIA inhibited both blast cells and CFU-GM. Purified spleen ferritin failed to inhibit blast progenitors or HL-60 cells at any concentration tested, but inhibited both 70-day and 14-day CFU-GM. Using the thymidine “suicide„ technique, the action of LIA was confirmed as being on CFU-GM in S-phase, but it failed to affect the proliferation of blast cell in S-phase. It is concluded that acidic isoferritins inhibit normal CFU-GM but not blast cells from patients with AML. Acidic isoferritins could confer a proliferative advantage of the leukemic clone over its normal counterparts.

Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 1025-1028 ◽  
Author(s):  
Jerome Tamburini ◽  
Caroline Elie ◽  
Valérie Bardet ◽  
Nicolas Chapuis ◽  
Sophie Park ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Myelogenous Leukemia ◽  
Akt Pathway ◽  
Pi3k Activation ◽  
Acute Myelogenous ◽  
Blast Cells ◽  
Targeted Inhibition ◽  
Phosphoinositide 3 Kinase

Abstract The phosphoinositide 3-kinase (PI3K/Akt) pathway is activated in acute myelogenous leukemia (AML) and is promising for targeted inhibition. Ninety-two patients with primary AML were analyzed for PI3K/Akt constitutive activation. Fifty percent of the patients presented with constitutive PI3K activation (PI3K +). No difference was observed between PI3K + and PI3K − groups concerning age, sex, white blood cell count, lactate dehydrogenase (LDH) level, bone marrow blast cells, French-American-British (FAB) classification, cytogenetics, RAS or nucleophosmin (NPM) mutations. Slightly more FLT3-ITD was detected in the PI3K − group (P = .048). The complete remission rate was similar between the 2 groups. With a median follow-up of 26 months, we observed for PI3K + and PI3K − patients, respectively, 56% and 33% overall survival (P = .001) and 72% and 41% relapse-free survival (P = .001). Constitutive PI3K/Akt activity is a favorable prognosis factor in AML, even after adjustment for FLT3-ITD, and may confer a particular sensitivity to chemotherapy. A better understanding of the downstream effectors of the PI3K/Akt pathway is needed before targeting in AML.

scholarly journals In vitro cytotoxicity of the LDE: daunorubicin complex in acute myelogenous leukemia blast cells

2001 ◽  
Vol 34 (10) ◽  
pp. 1257-1263 ◽  
Author(s):  
P.E. Dorlhiac-Llacer ◽  
M.V. Marquezini ◽  
O. Toffoletto ◽  
R.C.G. Carneiro ◽  
R.C. Maranhão ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
In Vitro Cytotoxicity ◽  
Myelogenous Leukemia ◽  
Leukemia Blast ◽  
Acute Myelogenous ◽  
Blast Cells
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