Caspase 2 and Caspase 3 Protein Levels as Predictors of Survival in Acute Myelogenous Leukemia

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3090-3097 ◽  
Author(s):  
Zeev Estrov ◽  
Peter F. Thall ◽  
Moshe Talpaz ◽  
Elihu H. Estey ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Acute Myelogenous Leukemia ◽  
Caspase 3 ◽  
Myelogenous Leukemia ◽  
Prognostic Variables ◽  
Normal Peripheral Blood ◽  
Protein Levels ◽  
Acute Myelogenous ◽  
Caspase 2 ◽  
High Level

Abstract Because caspase activation is an essential step in programmed cell death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by caspase 2 and caspase 3, we hypothesized that caspase 2 and 3 levels predict clinical outcome in acute myelogenous leukemia (AML). Using quantitative Western blot analysis, we studied the levels of nonactivated (uncleaved) caspase 2 and 3 in peripheral blood low-density cells from 185 patients with newly diagnosed AML. We also measured the level of activated (cleaved) caspase 3 in 41 randomly selected samples from the 185 patients. Finally, we analyzed the effect of caspase 2 and 3 levels and other prognostic variables on patient survival using a multivariate Cox model. We found that median levels of nonactivated caspase 2 and 3 were higher in AML than in normal peripheral blood cells (P < .001 and P <.02, respectively). There was no association between caspase level and either the percentage of peripheral blasts or any specific type of leukemia cell cytogenetic abnormalities. When the effect of each uncleaved caspase was considered individually, a high level of uncleaved caspase 3 (P = .04), but not of caspase 2 (P = .16), was associated with decreased survival. Conversely, a high level of cleaved caspase 3 denoted improved survival and correlated with the inactivation of the DNA-repair enzyme poly(ADP-ribose) polymerase. Thus, cleaved caspase 3 could stimulate the apoptotic cascade further, and lack of its activation likely caused an accumulation of the uncleaved caspase. Although uncleaved caspase 2 level per se had no prognostic significance, the interactive effect of high levels of both uncleaved caspase 2 and 3 denoted very poor survival (P < .001) and had the largest effect of all prognostic variables (P < .001; estimated relative risk, 2.49; 95% confidence interval, 1.59 to 3.90). Taken together, caspase 2 and caspase 3 protein levels obtained at diagnosis may constitute a reliable prognostic factor in AML. © 1998 by The American Society of Hematology.

Caspase 2 and Caspase 3 Protein Levels as Predictors of Survival in Acute Myelogenous Leukemia

Blood ◽  
1998 ◽  
Vol 92 (9) ◽  
pp. 3090-3097 ◽  
Author(s):  
Zeev Estrov ◽  
Peter F. Thall ◽  
Moshe Talpaz ◽  
Elihu H. Estey ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Acute Myelogenous Leukemia ◽  
Caspase 3 ◽  
Myelogenous Leukemia ◽  
Prognostic Variables ◽  
Normal Peripheral Blood ◽  
Protein Levels ◽  
Acute Myelogenous ◽  
Caspase 2 ◽  
High Level

Because caspase activation is an essential step in programmed cell death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by caspase 2 and caspase 3, we hypothesized that caspase 2 and 3 levels predict clinical outcome in acute myelogenous leukemia (AML). Using quantitative Western blot analysis, we studied the levels of nonactivated (uncleaved) caspase 2 and 3 in peripheral blood low-density cells from 185 patients with newly diagnosed AML. We also measured the level of activated (cleaved) caspase 3 in 41 randomly selected samples from the 185 patients. Finally, we analyzed the effect of caspase 2 and 3 levels and other prognostic variables on patient survival using a multivariate Cox model. We found that median levels of nonactivated caspase 2 and 3 were higher in AML than in normal peripheral blood cells (P < .001 and P <.02, respectively). There was no association between caspase level and either the percentage of peripheral blasts or any specific type of leukemia cell cytogenetic abnormalities. When the effect of each uncleaved caspase was considered individually, a high level of uncleaved caspase 3 (P = .04), but not of caspase 2 (P = .16), was associated with decreased survival. Conversely, a high level of cleaved caspase 3 denoted improved survival and correlated with the inactivation of the DNA-repair enzyme poly(ADP-ribose) polymerase. Thus, cleaved caspase 3 could stimulate the apoptotic cascade further, and lack of its activation likely caused an accumulation of the uncleaved caspase. Although uncleaved caspase 2 level per se had no prognostic significance, the interactive effect of high levels of both uncleaved caspase 2 and 3 denoted very poor survival (P < .001) and had the largest effect of all prognostic variables (P < .001; estimated relative risk, 2.49; 95% confidence interval, 1.59 to 3.90). Taken together, caspase 2 and caspase 3 protein levels obtained at diagnosis may constitute a reliable prognostic factor in AML. © 1998 by The American Society of Hematology.

Platelet functions and clinical effects in acute myelogenous leukemia

2008 ◽  
Vol 99 (01) ◽  
pp. 27-37 ◽  
Author(s):  
Øystein Bruserud ◽  
Brynjar Foss
Keyword(s):  
Peripheral Blood ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Clinical Effects ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Normal Peripheral Blood ◽  
Acute Myelogenous ◽  
Platelet Functions

SummaryPlatelets interact with normal peripheral blood cells via adhesion as well as soluble mediators, and platelet released mediators can affect hematopoietic stem and progenitor cells. Interactions may also be involved between platelets and circulating malignant cells, which is suggested by the effects platelets seem to have on metastasis and the various platelet abnormalities observed in various malignant disorders, including acute myelogenous leukemia (AML) and other leukemias. It is only recently that the interactions between platelets and AML cells have been characterized in detail, and studies show that; i) platelets and AML blasts can affect functional characteristic of each other, ii) chemotherapeutic drugs frequently used in AML therapy can alter several platelet functions, iii) the systemic levels of various cytokines are enhanced during AML chemotherapy, including cytokines known to affect both leukemic blasts and platelet activation, and iv) platelet secretion of growth factors are clearly detected in peripheral blood stem cells autografts. In this review we describe platelet interactions with normal leukocytes, normal hematopoietic and leukemic cells and the possible clinical relevance of these interactions in AML.

scholarly journals Irradiated B7-1 transduced primary acute myelogenous leukemia (AML) cells can be used as therapeutic vaccines in murine AML

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2938-2946 ◽  
Author(s):  
K Dunussi-Joannopoulos ◽  
HJ Weinstein ◽  
PW Nickerson ◽  
TB Strom ◽  
SJ Burakoff ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Myelogenous Leukemia ◽  
High Titer ◽  
Myelogenous Leukemia ◽  
Therapeutic Vaccines ◽  
Natural Ligand ◽  
Acute Myelogenous ◽  
High Level ◽  
Transformed Cell Lines

Recent studies have shown that tumor cells genetically modified by transduction of B7–1, a natural ligand for the T-cell costimulatory molecules CD28 and CTLA-4, are rejected in syngeneic hosts. In these reports, transformed cell lines and drug-selected cells have been used for vaccinations. To determine the effectiveness of B7–1-transduced primary acute myelogenous leukemia (AML) cells on the induction of antitumor immunity, we have studied a murine AML model in which primary AML cells were retrovirally transduced with the murine B7–1 cDNA. A defective retroviral producer clone expressing B7–1 and secreting a high titer of virus was used for infection of AML cells. Unselected transduced AML cells, expressing a high level of B7–1, were used for in vivo vaccinations. Our results show that one intravenous (IV) injection of irradiated B7–1-positive (B7–1+) AML cells can provide long-lasting (5 to 6 months) systemic immunity against subsequent challenge with wild-type AML cells. Furthermore, one exposure to irradiated B7–1+ AML cells results in rejection of leukemia by leukemic mice when the vaccination occurs in the early stages of the disease. The antileukemia immunity is CD8+ T-cell-dependent and B7/CD28-mediated, since in vivo treatment of mice with anti-CD8 monoclonal antibody or CTLA-4 Ig leads to abrogation of the specific antileukemia immune response. These results emphasize that B7–1 vaccines may have therapeutic usefulness for patients with AML.

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