scholarly journals Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia

Blood ◽  
1995 ◽  
Vol 85 (1) ◽  
pp. 186-193 ◽  
Author(s):  
E Schneider ◽  
KH Cowan ◽  
H Bader ◽  
S Toomey ◽  
GN Schwartz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Acute Leukemia ◽  
Internal Control ◽  
Bone Marrow Cells ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Paired Samples ◽  
Mdr1 Expression

Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine relative levels of transcripts for MDR1 and the recently described multidrug resistance-associated protein (MRP) in normal lymphohematopoietic cells and in 62 bone marrow aspirates of newly diagnosed and recurrent acute leukemia. Levels of MRP expression in newly diagnosed AML samples were similar to those observed in normal bone marrow cells (CD34-negative and CD34-positive) and in unselected HL60 human promyelocytic leukemia cells, which were used as an internal control throughout this study. In contrast, samples of AML obtained at the time of relapse contained approximately twofold higher levels of MRP RNA (P < .01). Analysis of paired samples, the first obtained at diagnosis and the second at relapse, from 13 acute myelogenous leukemia (AML) and four acute lymphocytic leukemia (ALL) patients showed that MRP expression was increased at the time of relapse in greater than 80% of patients. In contrast, no consistent changes of MDR1 expression at relapse were observed. These results raise the possibility that increased MRP expression might contribute to leukemic relapse.

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.

scholarly journals Autologous bone marrow transplantation in acute leukemia with marrow purged with alkyl-lysophospholipid

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1423-1429
Author(s):  
WR Vogler ◽  
WE Berdel ◽  
AC Olson ◽  
EF Winton ◽  
LT Heffner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Median Time ◽  
Bone Marrow Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Platelet Recovery ◽  
Autologous Bone

Alkyl-lysophospholipids are anticancer agents that are selectively toxic to leukemic cells and relatively sparing of normal bone marrow cells. Thus, they would be likely candidates for purging remission marrows before autologous bone marrow transplant. One of the more promising agents is edelfosine, which could be safely used for purging without prolonging marrow recovery. Assays for marrow progenitor cells were performed before and after purging and cryopreservation in 64 patients. There was no significant reduction in colony formation after purging when compared with unpurged cryopreserved marrow, but there was a significant reduction after cryopreservation. Twenty-four patients with acute leukemia in second (16 patients) or third remission (3 patients), early relapse (3 patients), or in first remission with successfully treated extramedullary relapse (2 patients) received marrow-ablative chemotherapy and total body irradiation followed by infusion of marrow purged for 4 hours with 50 to 100 micrograms/mL of edelfosine. There were 9 lymphoblastic and 15 myelogenous leukemia patients. The median time to granulocyte recovery to 500/microL was 26 and 33 days for the 50 and 75 microgram/mL doses, respectively. The patient whose marrow was purged at the dose of 100 micrograms/mL failed to engraft. The median time to platelet recovery to 25,000/microL was 45 and 37 days for the 50 and 75 micrograms/mL doses, respectively. Twenty-nine percent of the patients remain disease free from 131 to 1,291 days, with a median of 356 days. These results have established that purging with 75 micrograms/mL of edelfosine is a safe dose and is recommended for a phase II trial.

Oncogenic interaction between BCR-ABL andNUP98-HOXA9 demonstrated by the use of an in vitro purging culture system

Blood ◽  
2002 ◽  
Vol 100 (12) ◽  
pp. 4177-4184 ◽  
Author(s):  
Nadine Mayotte ◽  
Denis-Claude Roy ◽  
Jing Yao ◽  
Evert Kroon ◽  
Guy Sauvageau
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Disease Progression ◽  
Bone Marrow Cells ◽  
Myelogenous Leukemia ◽  
Mouse Bone Marrow ◽  
Genetic Level ◽  
Marrow Cells

Chronic myelogenous leukemia (CML) is a clonal stem cell disease caused by the BCR-ABL oncoprotein and is characterized, in its early phase, by excessive accumulation of mature myeloid cells, which eventually leads to acute leukemia. The genetic events involved in CML's progression to acute leukemia remain largely unknown. Recent studies have detected the presence of theNUP98-HOXA9 fusion oncogene in acute leukemia derived from CML patients, which suggests that these 2 oncoproteins may interact and influence CML disease progression. Using in vitro purging of BCR-ABL–transduced mouse bone marrow cells, we can now report that recipients of bone marrow cells engineered to coexpressBCR-ABL with NUP98-HOXA9 develop acute leukemia within 7 to 10 days after transplantation. However, no disease is detected for more than 2 months in mice receiving bone marrow cells expressing either BCR-ABL orNUP98-HOXA9. We also provide evidence of high levels ofHOXA9 expressed in leukemic blasts from acute-phase CML patients and that it interacts significantly on a genetic level withBCR-ABL in our in vivo CML model. Together, these studies support a causative, as opposed to a consequential, role forNUP98-HOXA9 (and possibly HOXA9) in CML disease progression.

Partially Mismatched Related-Donor Bone Marrow Transplantation for Pediatric Patients With Acute Leukemia: Younger Donors and Absence of Peripheral Blasts Improve Outcome

2000 ◽  
Vol 18 (9) ◽  
pp. 1856-1866 ◽  
Author(s):  
K.T. Godder ◽  
L.J. Hazlett ◽  
S.H. Abhyankar ◽  
K.Y. Chiang ◽  
N.P. Christiansen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Acute Leukemia ◽  
Marrow Transplantation ◽  
Pediatric Patients ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Pediatric Leukemia ◽  
Total Body

PURPOSE: To extend access to bone marrow transplantation (BMT), we used partially mismatched related donors (PMRD) for pediatric patients with acute leukemia. In this report we sought to determine pretransplantation factors that might predict outcome. PATIENTS AND METHODS: Of 67 such patients, 43 had acute lymphocytic leukemia and 24 had acute myelogenous leukemia. At the time of transplantation, 41 patients were in relapse. Donors included 40 parents, 24 siblings, and three cousins. HLA disparity of two to three major antigens was detected in two thirds of the donor-recipient pairs. Conditioning therapy, including total-body irradiation and chemotherapy followed by graft-versus-host disease (GvHD) prophylaxis with partial T-cell depletion of the graft using T10B9 or OKT3, was combined with posttransplantation immunosuppression. RESULTS: Estimated probability (EP) of engraftment was 0.96 and was not affected by donor-antigen mismatch (AgMM; P = .732). EP of grades 2 to 4 acute GvHD was 0.24 and was not affected by recipient AgMM (P = .796). EP of disease-free survival was 0.26 at 3 years but improved to 0.45 when donors were younger than 30 years (P < .001). EP of relapse at 3 years was 0.41 and reduced with younger donors’ age. For patients who were in relapse at the time of transplantation, absence of blasts was associated with a lower relapse rate (0.46 v 0.84; P = .083), similar to that of patients in remission. CONCLUSION: PMRD-BMT in pediatric leukemia resulted in high engraftment and low GvHD rates. To improve outcomes, younger donors should be sought, and clinicians should attempt to reduce peripheral blasts in patients who are in relapse.

scholarly journals Differences in Inducing Activity for Human Bone Marrow Colonies in Normal Serum and Serum From Patients With Leukemia

Blood ◽  
1973 ◽  
Vol 42 (3) ◽  
pp. 331-339 ◽  
Author(s):  
Uri Mintz ◽  
Leo Sachs
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Normal Activity ◽  
Normal Serum ◽  
Lymphocytic Leukemia ◽  
Human Bone ◽  
Human Bone Marrow ◽  
High Concentration

Abstract Normal serum and serums from patients with acute and chronic leukemia were assayed for granulocyte colony-inducing activity with human bone marrow cells. Serum from untreated acute leukemia, but not from the other patients, showed about normal inducing activity at low serum concentration and lower than normal activity at high concentration. This suggests that serum from patients with acute leukemia contained an inhibitor for colony formation. Serums from chronic myeloid leukemia were in about the same range as normal, whereas serums from chronic lymphocytic leukemia showed the highest colony-inducing activity.

DNA-RNA measurements in patients with acute leukemia undergoing remission induction therapy.

1985 ◽  
Vol 3 (6) ◽  
pp. 799-808 ◽  
Author(s):  
A M Maddox ◽  
D A Johnston ◽  
B Barlogie ◽  
E Youness ◽  
M Keating ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
S Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
Bone Marrow Biopsies ◽  
Long Duration ◽  
Acute Myelogenous ◽  
The Mean

Prior to therapy, 111 newly diagnosed adult patients with acute leukemia had DNA content measured (cell-cycle distributions) and 91 had RNA content measured using flow cytometry of acridine orange-stained bone marrow biopsies. The RNA index (RI) (ratio of mean RNA in G0/G1 of the sample to the median RNA in G0/G1 of normal lymphocytes) distinguished acute myelogenous leukemia (AML) from acute lymphocytic leukemia (ALL). The mean RI in AML was 2.2 and in ALL 1.5. RI did not predict for achievement of complete remission (CR). In AML the mean S-phase percent was 11.2 in patients who achieved CR and 13.1 in those who failed to respond to therapy, whereas in ALL it was 14.5 in those responding and 8.0 in those not responding (P = .02). In the 77 patients with either AML or ALL who achieved CR, a low pretreatment S-phase percent and a high RI correlated with a long duration of CR. S-phase percent and RI were also measured during remission induction and during maintenance therapy. Between days 8 and 18, the RI of responders decreased. In both AML and ALL an increase in S-phase percent between days 18 and 22, prior to morphological CR, was observed in responders but not in nonresponders. The mean S-phase percent at the time of morphological remission was 17.3. A high S-phase percent at this time correlated with a longer duration of CR. Although neither pretreatment S-phase percent nor RI was found to predict for achievement of CR in AML, both predicted for length of CR. Increases in S-phase percent during therapy indicated recovery of normal hematopoiesis.

scholarly journals Autologous bone marrow transplantation in acute leukemia with marrow purged with alkyl-lysophospholipid

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1423-1429 ◽  
Author(s):  
WR Vogler ◽  
WE Berdel ◽  
AC Olson ◽  
EF Winton ◽  
LT Heffner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Median Time ◽  
Bone Marrow Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Platelet Recovery ◽  
Autologous Bone

Abstract Alkyl-lysophospholipids are anticancer agents that are selectively toxic to leukemic cells and relatively sparing of normal bone marrow cells. Thus, they would be likely candidates for purging remission marrows before autologous bone marrow transplant. One of the more promising agents is edelfosine, which could be safely used for purging without prolonging marrow recovery. Assays for marrow progenitor cells were performed before and after purging and cryopreservation in 64 patients. There was no significant reduction in colony formation after purging when compared with unpurged cryopreserved marrow, but there was a significant reduction after cryopreservation. Twenty-four patients with acute leukemia in second (16 patients) or third remission (3 patients), early relapse (3 patients), or in first remission with successfully treated extramedullary relapse (2 patients) received marrow-ablative chemotherapy and total body irradiation followed by infusion of marrow purged for 4 hours with 50 to 100 micrograms/mL of edelfosine. There were 9 lymphoblastic and 15 myelogenous leukemia patients. The median time to granulocyte recovery to 500/microL was 26 and 33 days for the 50 and 75 microgram/mL doses, respectively. The patient whose marrow was purged at the dose of 100 micrograms/mL failed to engraft. The median time to platelet recovery to 25,000/microL was 45 and 37 days for the 50 and 75 micrograms/mL doses, respectively. Twenty-nine percent of the patients remain disease free from 131 to 1,291 days, with a median of 356 days. These results have established that purging with 75 micrograms/mL of edelfosine is a safe dose and is recommended for a phase II trial.

scholarly journals Premature chromosome condensation studies in human leukemia. I. Pretreatment characteristics

Blood ◽  
1979 ◽  
Vol 54 (5) ◽  
pp. 1001-1014 ◽  
Author(s):  
WN Hittelman ◽  
LC Broussard ◽  
K McCredie
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chromosome Condensation ◽  
S Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Proliferative Potential ◽  
Human Leukemia ◽  
Premature Chromosome Condensation ◽  
G1 Cells

The phenomenon of premature chromosome condensation (PCC) was used to compare the bone marrow proliferation characteristics of 163 patients with various forms of leukemia prior to the initiation of new therapy. The proliferative potential index (PPI, or fraction of G1 cells in late G1 phase) and the fraction of cells in S phase was determined and compared to the type of disease and the bone marrow blast infiltrate for each patient. Previously untreated patients with acute leukemia exhibited an average PPI value three times that of normal bone marrow (37.5% for acute myeloblastic leukemia [AML], acute monomyeloblastic leukemia [AMML], or acute promyelocytic leukemia [APML] and 42% for acute lymphocytic leukemia [ALL] or acute undifferentiated leukemia [AUL]). Untreated chronic myelogenous leukemia (CML) patients showed intermediate PPI values (25.2%), whereas CML patients with controlled disease exhibited nearly normal PPI values (14.6%). On the other hand, blastic-phase CML patients exhibited PPI values closer to that observed in patients with acute leukemia (35.4%). Seven patients with chronic lymphocytic leukemia (CLL) exhibited even higher PPI values. No correlations were observed between PPI values, fraction of cells in S phase, and marrow blast infiltrate. For untreated acute disease patients, PPI values were prognostic for response only at low and high PPI values. These results suggest that the PCC-determined proliferative potential is a biologic reflection of the degree of malignancy within the bone marrow.

scholarly journals Premature chromosome condensation studies in human leukemia. I. Pretreatment characteristics

Blood ◽  
1979 ◽  
Vol 54 (5) ◽  
pp. 1001-1014 ◽  
Author(s):  
WN Hittelman ◽  
LC Broussard ◽  
K McCredie
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chromosome Condensation ◽  
S Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Proliferative Potential ◽  
Human Leukemia ◽  
Premature Chromosome Condensation ◽  
G1 Cells

Abstract The phenomenon of premature chromosome condensation (PCC) was used to compare the bone marrow proliferation characteristics of 163 patients with various forms of leukemia prior to the initiation of new therapy. The proliferative potential index (PPI, or fraction of G1 cells in late G1 phase) and the fraction of cells in S phase was determined and compared to the type of disease and the bone marrow blast infiltrate for each patient. Previously untreated patients with acute leukemia exhibited an average PPI value three times that of normal bone marrow (37.5% for acute myeloblastic leukemia [AML], acute monomyeloblastic leukemia [AMML], or acute promyelocytic leukemia [APML] and 42% for acute lymphocytic leukemia [ALL] or acute undifferentiated leukemia [AUL]). Untreated chronic myelogenous leukemia (CML) patients showed intermediate PPI values (25.2%), whereas CML patients with controlled disease exhibited nearly normal PPI values (14.6%). On the other hand, blastic-phase CML patients exhibited PPI values closer to that observed in patients with acute leukemia (35.4%). Seven patients with chronic lymphocytic leukemia (CLL) exhibited even higher PPI values. No correlations were observed between PPI values, fraction of cells in S phase, and marrow blast infiltrate. For untreated acute disease patients, PPI values were prognostic for response only at low and high PPI values. These results suggest that the PCC-determined proliferative potential is a biologic reflection of the degree of malignancy within the bone marrow.

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.

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