scholarly journals Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time of Leukemic Relapse

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 991-1000 ◽  
Author(s):  
Scott H. Kaufmann ◽  
Judith E. Karp ◽  
Phyllis A. Svingen ◽  
Stan Krajewski ◽  
Philip J. Burke ◽  
...  
Keyword(s):  
Initial Therapy ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Paired Samples ◽  
Elevated Expression ◽  
Leukemic Relapse ◽  
Acute Myelogenous ◽  
Weak Negative Correlation ◽  
Apoptosis Inhibitor

Abstract Bcl-2, Bcl-xL, and Mcl-1 are three related intracellular polypeptides that have been implicated as negative regulators of apoptosis. In contrast, the partner protein Bax acts as a positive regulator of apoptosis. Based on the observation that all four of these polypeptides are expressed in a variety of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) cell lines, cellular levels of these polypeptides were examined by immunoblotting in bone marrow samples harvested from 123 adult AML patients and 36 adult ALL patients before initial antileukemic therapy. Levels of Bcl-2, Mcl-1, Bcl-xL, and Bax each varied over a more than 10-fold range in different pretreatment leukemia specimens. When the 54 AML and 23 ALL samples that contained greater than 80% malignant cells were examined in greater detail, it was observed that pretreatment levels of Bcl-2 and Mcl-1 correlated with each other (R = .44,P < .001 for AML and R = .79,P < .0001 for ALL). In addition, a weak negative correlation between Bax expression and age was observed in AML samples (R = −0.35, P < .02) but not ALL samples. There was no relationship between pretreatment levels of these polypeptides and response to initial therapy. However, examination of 19 paired samples (the first harvested before chemotherapy and the second harvested 23 to 290 days later at the time of leukemic recurrence) revealed a greater than or equal to twofold increase in Mcl-1 levels in 10 of 19 pairs (7 of 15 AML and 3 of 4 ALL) at recurrence. In contrast, 2 of 19 pairs contained twofold less Mcl-1 at the time of recurrence. Approximately equal numbers of samples showed twofold increases and decreases in Bcl-2 (5 increases, 3 decreases) and Bcl-xL (1 increase, 4 decreases) at recurrence. Bax levels did not show a twofold decrease in any patient. These results, coupled with recent observations that cells overexpressing Mcl-1 are resistant to a variety of chemotherapeutic agents, raise the possibility that some chemotherapeutic regimens might select for leukemia cells with elevated levels of this particular apoptosis inhibitor.

scholarly journals Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time of Leukemic Relapse

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 991-1000 ◽  
Author(s):  
Scott H. Kaufmann ◽  
Judith E. Karp ◽  
Phyllis A. Svingen ◽  
Stan Krajewski ◽  
Philip J. Burke ◽  
...  
Keyword(s):  
Initial Therapy ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Paired Samples ◽  
Elevated Expression ◽  
Leukemic Relapse ◽  
Acute Myelogenous ◽  
Weak Negative Correlation ◽  
Apoptosis Inhibitor

Bcl-2, Bcl-xL, and Mcl-1 are three related intracellular polypeptides that have been implicated as negative regulators of apoptosis. In contrast, the partner protein Bax acts as a positive regulator of apoptosis. Based on the observation that all four of these polypeptides are expressed in a variety of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) cell lines, cellular levels of these polypeptides were examined by immunoblotting in bone marrow samples harvested from 123 adult AML patients and 36 adult ALL patients before initial antileukemic therapy. Levels of Bcl-2, Mcl-1, Bcl-xL, and Bax each varied over a more than 10-fold range in different pretreatment leukemia specimens. When the 54 AML and 23 ALL samples that contained greater than 80% malignant cells were examined in greater detail, it was observed that pretreatment levels of Bcl-2 and Mcl-1 correlated with each other (R = .44,P < .001 for AML and R = .79,P < .0001 for ALL). In addition, a weak negative correlation between Bax expression and age was observed in AML samples (R = −0.35, P < .02) but not ALL samples. There was no relationship between pretreatment levels of these polypeptides and response to initial therapy. However, examination of 19 paired samples (the first harvested before chemotherapy and the second harvested 23 to 290 days later at the time of leukemic recurrence) revealed a greater than or equal to twofold increase in Mcl-1 levels in 10 of 19 pairs (7 of 15 AML and 3 of 4 ALL) at recurrence. In contrast, 2 of 19 pairs contained twofold less Mcl-1 at the time of recurrence. Approximately equal numbers of samples showed twofold increases and decreases in Bcl-2 (5 increases, 3 decreases) and Bcl-xL (1 increase, 4 decreases) at recurrence. Bax levels did not show a twofold decrease in any patient. These results, coupled with recent observations that cells overexpressing Mcl-1 are resistant to a variety of chemotherapeutic agents, raise the possibility that some chemotherapeutic regimens might select for leukemia cells with elevated levels of this particular apoptosis inhibitor.

Evaluation of Apaf-1 and procaspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3922-3931 ◽  
Author(s):  
Phyllis A. Svingen ◽  
Judith E. Karp ◽  
Stan Krajewski ◽  
Peter W. Mesner ◽  
Steven D. Gore ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Prognostic Markers ◽  
Cysteine Proteases ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Paired Samples ◽  
Initiator Caspases ◽  
Cast Doubt ◽  
Acute Myelogenous ◽  
Highly Correlated

Recent studies have suggested that variations in levels of caspases, a family of intracellular cysteine proteases, can profoundly affect the ability of cells to undergo apoptosis. In this study, immunoblotting was used to examine levels of apoptotic protease activating factor-1 (Apaf-1) and procaspases-2, -3, -7, -8, and -9 in bone marrow samples (at least 80% leukemia) harvested before chemotherapy from adults with newly diagnosed acute myelogenous leukemia (AML, 42 patients) and acute lymphocytic leukemia (ALL, 18 patients). Levels of each of these polypeptides varied over a more than 10-fold range between specimens. In AML samples, expression of procaspase-2 correlated with levels of Apaf-1 (Rs = 0.52, P < .02), procaspase-3 (Rs = 0.56,P < .006) and procaspase-8 (Rs = 0.64, P < .002). In ALL samples, expression of procaspases-7 and -9 was highly correlated (Rs = 0.90,P < .003). Levels of these polypeptides did not correlate with prognostic factors or response to induction chemotherapy. In further studies, 16 paired samples (13 AML, 3 ALL), the first harvested before induction therapy and the second harvested at the time of leukemia regrowth, were also examined. There were no systematic alterations in levels of Apaf-1 or procaspases at relapse compared with diagnosis. These results indicate that levels of initiator caspases vary widely among different leukemia specimens but cast doubt on the hypothesis that this variation is a major determinant of drug sensitivity for acute leukemia in the clinical setting.

Evaluation of Apaf-1 and procaspases-2, -3, -7, -8, and -9 as potential prognostic markers in acute leukemia

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3922-3931 ◽  
Author(s):  
Phyllis A. Svingen ◽  
Judith E. Karp ◽  
Stan Krajewski ◽  
Peter W. Mesner ◽  
Steven D. Gore ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Prognostic Markers ◽  
Cysteine Proteases ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Paired Samples ◽  
Initiator Caspases ◽  
Cast Doubt ◽  
Acute Myelogenous ◽  
Highly Correlated

Abstract Recent studies have suggested that variations in levels of caspases, a family of intracellular cysteine proteases, can profoundly affect the ability of cells to undergo apoptosis. In this study, immunoblotting was used to examine levels of apoptotic protease activating factor-1 (Apaf-1) and procaspases-2, -3, -7, -8, and -9 in bone marrow samples (at least 80% leukemia) harvested before chemotherapy from adults with newly diagnosed acute myelogenous leukemia (AML, 42 patients) and acute lymphocytic leukemia (ALL, 18 patients). Levels of each of these polypeptides varied over a more than 10-fold range between specimens. In AML samples, expression of procaspase-2 correlated with levels of Apaf-1 (Rs = 0.52, P &lt; .02), procaspase-3 (Rs = 0.56,P &lt; .006) and procaspase-8 (Rs = 0.64, P &lt; .002). In ALL samples, expression of procaspases-7 and -9 was highly correlated (Rs = 0.90,P &lt; .003). Levels of these polypeptides did not correlate with prognostic factors or response to induction chemotherapy. In further studies, 16 paired samples (13 AML, 3 ALL), the first harvested before induction therapy and the second harvested at the time of leukemia regrowth, were also examined. There were no systematic alterations in levels of Apaf-1 or procaspases at relapse compared with diagnosis. These results indicate that levels of initiator caspases vary widely among different leukemia specimens but cast doubt on the hypothesis that this variation is a major determinant of drug sensitivity for acute leukemia in the clinical setting.

scholarly journals Leukemic relapse 5 1/2 years after allogeneic bone marrow transplantation

Blood ◽  
1978 ◽  
Vol 52 (2) ◽  
pp. 281-284 ◽  
Author(s):  
A Oliff ◽  
NP Ramu ◽  
D Poplack
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Extramedullary Relapse ◽  
Leukemic Relapse ◽  
Acute Myelogenous

Abstract A 13-yr-old male with acute myelogenous leukemia was treated with various chemotherapy regimens for 3 1/2 yr and then underwent an allogeneic bone marrow transplantation. The donor marrow was successfully engrafted, and the patient remained in remission free of all chemotherapy. Then, 5 1/2 yr later, he developed an extramedullary relapse with a chloroma of his maxillary sinus. This case illustrates the need for prolonged followup of transplant recipients and suggest that statements proposing cure as a result of this procedure may be premature.

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 NUTRITIONALLY VARIANT STREPTOCOCCI BACTEREMIA IN CANCER PATIENTS: A RETROSPECTIVE STUDY, 1999-2014

2015 ◽  
Vol 7 ◽  
pp. e2015030 ◽  
Author(s):  
Abraham Tareq Yacoub ◽  
Jayasree Krishnan ◽  
Ileana M. Acevedo ◽  
Joseph Halliday ◽  
John Norman Greene
Keyword(s):  
Cancer Patients ◽  
Clinical Characteristics ◽  
Blood Stream Infection ◽  
Hematologic Malignancies ◽  
Blood Stream ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Cancer Center ◽  
Underlying Malignancy ◽  
Acute Myelogenous

BackgoundNutritionally variant Streptococci (NVS), Abiotrophia and Granulicatella are implicated in causing endocarditis and blood stream infections more frequently than other sites of infection. Neutropenia and mucositis are the most common predisposing factors for infection with other pathogens in cancer patients. In this study we investigated the clinical characteristics of NVS bacteremia in cancer patients and identified risk factors and outcomes associated with these infections. Materials and MethodsWe retrospectively reviewed all cases of NVS bacteremia occurring from June 1999 to April 2014 at H. Lee Moffitt Cancer Center and Research Institute. The computerized epidemiology report provided by the microbiology laboratory identified thirteen cancer patients with NVS bacteremia. We collected data regarding baseline demographics and clinical characteristics such as age, sex, underlying malignancy, neutropenic status, duration of neutropenia, treatment, and outcome.ResultsThirteen patients were identified with positive NVS blood stream infection. Ten patients (77%) had hematologic malignancies, including chronic lymphocytic leukemia (CLL) (1), multiple myeloma (MM) (1), acute myelogenous leukemia (AML) (4), and non Hodgkin’s lymphoma (NHL) (4).  The non-hematologic malignancies included esophageal cancer (2) and bladder cancer (1).ConclusionNVS should be considered as a possible agent of bacteremia in cancer patients with neutropenia and a breach in oral, gastrointestinal and genitourinary mucosa (gingivitis/mucositis).

High peripheral blast count in adult acute myelogenous leukemia is a primary risk factor for CNS leukemia.

1988 ◽  
Vol 6 (3) ◽  
pp. 495-498 ◽  
Author(s):  
P A Cassileth ◽  
L S Sylvester ◽  
J M Bennett ◽  
C B Begg
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Eastern Cooperative Oncology Group ◽  
Myelogenous Leukemia ◽  
Cell Counts ◽  
Number Of Factors ◽  
Increased Risk ◽  
Leukemic Relapse ◽  
Acute Myelogenous ◽  
Blast Count ◽  
Low Incidence

The lengthening remission duration achievable in acute myelogenous leukemia (AML) places patients at risks for CNS leukemic relapse. We reviewed the data on two Eastern Cooperative Oncology Group (ECOG) trials in acute nonlymphocytic leukemia to determine the incidence of CNS leukemia (CNSL). The incidence of CNSL was 5% (30 of 569 patients) overall, and 3% (ten of 331) in patients in complete remission (CR). A number of factors were evaluated for association with increased risk of CNSL. Men more frequently developed CNSL than women at a three to one ratio, and median presenting WBC counts were higher in affected than unaffected patients (44,200/microL v 17,000/microL, P = .01). The low incidence of CNSL in AML supports the view that CNS prophylaxis is unnecessary. However, because 68% of patients (13 of 19) who developed CNSL early in the course of disease had presenting WBC counts greater than 40,000/microL, screening lumbar punctures should be routinely obtained during induction therapy in patients presenting with high circulating blast cell counts.

Elevated serum ras level predicts decreased survival in patients with hematologic malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6562-6562 ◽  
Author(s):  
E. M. Nelli ◽  
K. Leitzel ◽  
S. M. Ali ◽  
H. A. Al-Mondhiry ◽  
L. Demers ◽  
...  
Keyword(s):  
Overall Survival ◽  
Patient Group ◽  
Acute Myelogenous Leukemia ◽  
Elevated Serum ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ras Signaling ◽  
Potential Biomarker ◽  
Acute Myelogenous

6562 Background: Ras is a GDP/GTP binding G protein that acts as a molecular switch converting signals from the cell membrane to the nucleus to regulate cell proliferation, differentiation, and protein synthesis. Activation of ras oncogenes has been identified in a variety of cancers, including 30% of acute myelogenous leukemia patients. The purpose of our study was to evaluate serum ras levels and correlate with survival in hematologic cancer patients. Methods: A novel ras p21 ELISA (Oncogene Science/Bayer Diagnostics, Cambridge, MA) employing two monoclonal antibodies reactive with H, K, and N ras was utilized to quantify total ras levels in serum obtained from patients with various hematologic malignancies including acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL). Results: The total leukemia patient group consisted of 52 patients. At the 75th percentile serum ras cutpoint (524 pg/ml) 11/52 patients were defined as elevated for serum ras. From this patient group, 38 patients had clinical followup available and were included in the Kaplan-Meier analysis of overall survival. Patients with elevated serum ras (>524 pg/ml) had significantly shorter overall survival compared to those without (median OS 205 vs. 677 days) (p= 0.04). In a multivariate analysis including serum ras level and type of leukemia, serum ras level remained a significant independent variable for shorter overall survival (p=0.004). Within leukemia subtypes 2/18 AML, 4/9 CML, 3/7 ALL, and 0/4 CLL patients had elevated serum ras levels. Conclusions: Leukemia patients with elevated serum ras levels had a significantly shorter overall survival. Serum ras should be evaluated as a potential biomarker in larger leukemia trials, especially for response to treatment with inhibitors of the ras signaling pathway. [Table: see text]

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