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 De novo appearance of the ph-1 chromosome in a previously monosomic bone marrow (45,XX,-6): conversion of a myeloproliferative disorder to acute myelogenous leukemia

Blood ◽  
1975 ◽  
Vol 45 (5) ◽  
pp. 653-657 ◽  
Author(s):  
G Kohn ◽  
N Manny ◽  
A Eldor ◽  
MM Cohen
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Bone Marrow Examination ◽  
Myeloproliferative Disorder ◽  
Myelogenous Leukemia ◽  
Aneuploid Cell ◽  
Blastic Crisis ◽  
Acute Myelogenous

Abstract Bone marrow examination of a patient with a myeloproliferative disorder revealed monosomy for chromosome No. 6 (45,XX,-6). Two months later, during blastic crisis, reinvestigation of the bone marrow showed the presence of the Ph-1 chromosome in the previously aneuploid cell line (45,XX,-6,-22,+Ph-1). This case differs from those previously published in that the Ph-1 chromosome appeared de novo during the development of frank acute myelogenous leukemia.

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.

Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1202-1210 ◽  
Author(s):  
Eric Solary ◽  
Bernard Drenou ◽  
Lydia Campos ◽  
Patricia de Crémoux ◽  
Francine Mugneret ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Complete Remission ◽  
Significant Influence ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
P Glycoprotein ◽  
Acute Myelogenous ◽  
The Mean

Abstract Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein–mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n = 213) or did not receive (n = 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% ± 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P = .01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

Homoharringtonine Based Triple-Drug Regimen as Induction Chemotherapy for De Novo Acute Myelogenous Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2002-2002
Author(s):  
Jie Jin ◽  
Wenbin Qian ◽  
Hui Liu ◽  
Daozi Jian ◽  
Wenyuan Mai ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Neutrophil Count ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Acute Myelogenous ◽  
De Novo Aml

Abstract HAA regimen, consisting of homoharringtonine (HHT), aclarubicin and cytarabine (Ara-C), is an efficacious chemotherapy regimen for induction treatment of acute myelogenous leukemia (AML). HHT, a plant alkaloid that is derived from a Chinese evergreen tree, has been shown to inhibit protein, DNA, and RNA synthesis by inhibition of chain initiation. HAA regimen consists of HHT administered at a dose of 4 mg/m2/day by continuous infusion over 4 hours or 2 mg/m2 intramuscular injection twice daily on days 1–3, aclarubicin administered at a dose of 12 mg/m2/day by continuous infusion over 2 hours on days 1–7, and cytarabine (Ara-C) given at a dose of 75 mg/m2 twice daily on days 1–7. Granulocyte colony-stimulating factor (Lenograstim) 5 μg/kg/day subcutaneously was started from the day neutrophil count <0.5×109/l, and continued until the day neutrophil count >1.0×109/l on 3 successive days. For patients with partial remission (PR) after the evaluation of the first course of the therapy, another same induction HAA regimen was administered. Between May 1999 and June 2006, 80 patients consisted of 31 male and 49 female patients were enrolled. All patients had newly diagnosed with de novo AML and had not received any induction treatments before. Out of them, 3 were M1, 44 M2, 2 M4, and 31 M5 according to FAB classification criteria. The median age was 36 (14–59) years. Of all the 76 patients with cytogenetic analysis available, 13 had favorable karyotype, 58 intermediate karyotype, and 5 unfavorable karyotype. In all, 68 (85%) patients achieved complete remission (CR), and the first single course of this induction regimen resulted in a CR rate of 75%. The CR rate of 100%, 88% and 20% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. We also found that patients with M5 achieved a CR rate of 74% (23/31), while patients with M1 or M2 94% (44/47). The toxicities associated with this regimen were no more than those expected with standard chemotherapy, and the most common non-hematological toxicity was infection. This study suggested that HAA regimen is a safe regimen and it is efficacious, well-tolerable induction therapy for newly diagnosed de novo AML, the use of G-CSF (Lenograstim) appears to be safe, with little risk of accelerating leukemic relapse. A high CR rate can be achieved with only one or two courses of this regimen. Besides, cytogenetics is an important prognostic factor.

Combination Methyltransferase and Histone Deacetylase Inhibition in Elderly Patients with Secondary Acute Myelogenous Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4387-4387 ◽  
Author(s):  
Chandanda Thatikonda ◽  
James M. Rossetti ◽  
Richard K. Shadduck ◽  
John Lister
Keyword(s):  
Elderly Patients ◽  
Histone Deacetylase ◽  
Acute Myelogenous Leukemia ◽  
De Novo ◽  
Symptomatic Relief ◽  
Myelogenous Leukemia ◽  
Platelet Response ◽  
Trisomy 8 ◽  
Secondary Aml ◽  
Acute Myelogenous

Abstract Background: Secondary acute myelogenous leukemia (AML) carries a poor prognosis when compared to de novo AML. Therapeutic options are typically limited as patients are often elderly with comorbidities that preclude intensive chemotherapy. Moreover, resistance to therapy is common. Studies have shown that methyltransferase inhibitors (MTI) have activity in myeloid malignancy. It is not known if addition of histone deacetylase (HDAC) inhibitors improves or prolongs the activity of MTI. We present our experience of 3 elderly patients with secondary AML treated with MTI (azacitidine or decitabine) in combination with an HDAC inhibitor (vorinostat). Methods: Patients include 2 males and 1 female, ages 78 yrs, 82 yrs and 71 yrs. All were initially diagnosed with high-grade myelodysplastic syndrome (MDS), which transformed to CD34+ secondary AML at 33, 14 and 4 months from diagnosis of MDS, respectively. One patient had trisomy 8. Patients received 8, 3 and 4 cycles of MTI before leukemic transformation, respectively. At transformation, one patient failed standard induction therapy and 1 patient failed arsenic trioxide. Both of these patients were then placed back on MTI as maintenance therapy. Vorinostat was added at a dosage of 400 mg daily at MTI cycles 8, 3 and 1 post transformation, respectively. The number of cycles of combination therapy was 6, 9 and 4. Gastrointestinal intolerance was an issue in 2 of these patients: nausea (n=2), diarrhea (n=2), vomiting (n=1) and loss of appetite (n=1). Dose reduction to 100mg in one patient and 300 mg in another resulted in some symptomatic relief. The addition of 5-HT3 antagonists or low dose prednisone allowed dose escalation. One patient had 50% reduction in marrow blasts, 1 had near clearance of the peripheral blasts and 1 had a transient minor platelet response. All 3 patients are alive at 14, 10 and 9 months post transformation (6, 8 and 7 months after addition of vorinostat) with no disease progression, respectively. Conclusion: The combination of MTI and HDAC could be an option in elderly patients with secondary AML without increasing morbidity and mortality. Treatment appears well tolerated when premedication with 5-HT3 antagonists is employed. As the treatment options are limited in high-risk elderly patients with secondary AML, larger studies are needed to investigate the utility of this combination.

The pp90rsk-CREB Signaling Pathway Regulates Apoptosis In Acute Myelogenous Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3801-3801
Author(s):  
Bryan Mitton ◽  
Ritika Dutta ◽  
Yu-Chiao Hsu ◽  
Rachel Ochoa ◽  
Elliot Landaw ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Apoptosis ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Expression Level ◽  
Acute Myelogenous ◽  
Targeted Inhibition ◽  
Induced Apoptosis ◽  
Pharmacologic Inhibition

Abstract CREB (cAMP Response-Element Binding Protein) is a nuclear transcription factor critical for hematopoietic cell proliferation, differentiation, and survival. We previously demonstrated that 60% of patients with Acute Myelogenous Leukemia (AML) overexpress CREB in leukemic blasts, and CREB overexpression in these patients was associated with an increased risk of relapse and decreased event-free survival. Previous studies have suggested that CREB may play an important role in the regulation of apoptosis in a wide variety of cancers. Specifically, CREB has been shown to up-regulate members the anti-apoptotic protein family such as Bcl-2, Bcl-XL and Mcl-1, leading to chemotherapy resistance in vitro. CREB-mediated resistance to apoptosis may underlie the increased rate of relapse and poor survival of AML patients with CREB overexpression. Thus, we hypothesized that targeted inhibition of CREB in AML cells would promote AML cell apoptosis. To test this hypothesis, we developed a small-molecule inhibitor of CREB function, XX-650-23. This molecule disrupts the interaction between CREB and its binding partner CBP (CREB-Binding Protein), which is required for full activation of CREB-mediated gene transcription. Treatment of primary AML patient bone marrow samples with XX-650-23 induced apoptosis and cell death at a dose of 2 uM. The degree of apoptosis varied with the expression level of CREB in primary AML cells tested. Higher CREB levels correlated with higher sensitivity to XX-650-23. In non-leukemic primary patient bone marrow samples, CREB levels were very low, and XX-650-23 did not induce apoptosis in these cells. AML cell lines (KG-1 and HL-60) also underwent apoptosis following CREB inhibition, in proportion to CREB expression level. CREB knockdown or overexpression in KG-1 cells decreased and increased susceptibility to apoptosis, respectively. Mechanistically, the onset of apoptosis in AML cells occurred simultaneously with down-regulation of Bcl-2, a validated CREB-regulated gene. Inhibition of Bcl-2 function using the specific Bcl-2 inhibitor ABT-737 (100 nM) induced apoptosis similar to XX-650-23, indicating that Bcl-2 inhibition alone is sufficient to cause apoptosis. Thus, targeted inhibition of CREB results in Bcl-2 downregulation and is sufficient to induce apoptosis in AML cells. Proteomic analysis using Mass Cytometry-Time of Flight (CyTOF) revealed that one compensatory cellular response to CREB inhibition is increased phosphorylation of CREB. This phosphorylation decreased in the presence of BI-D1870, a specific inhibitor of the pp90RSK kinase (RSK), but not by pharmacologic inhibition of the p38 or ERK kinases, using SB202190 or U0126, respectively. We therefore examined the role of pp90RSK in the regulation of apoptosis in AML cells. Pharmacologic inhibition of RSK independently lead to AML cell apoptosis (BI-D1870, IC50=3.3 uM), in part due to blockade of CREB phosphorylation. In summary, our data provide the first evidence that inhibition of CREB, or its chief activator RSK, is sufficient to induce apoptosis in AML cells. Current work focuses on defining CREB target genes mediating XX-650-23 response using chromatin-immunoprecipitation with massively parallel DNA sequencing (ChIP-Seq), and defining the RSK kinome in AML cells using 2-dimensional gel phosphoprotein profiling. These studies will more fully define the role of the RSK-CREB signaling axis in AML proliferation, survival, and apoptosis. Disclosures: No relevant conflicts of interest to declare.

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.

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