Detection of Acute Myeloid Leukemic Cells in Complete Remission and in Extramedullary Sites by Clonal Analyses

Schmetzer, Helga; Wilmanns, W.; Gerhartz, H.

doi:10.1159/000203721

Cited by 9 publications

(8 citation statements)

References 5 publications

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“…With this method, the leukemic tumor load of untreated BM samples as well as of BM cells after cytokine treatment and/or LAK cell treatment was evaluated. As in previous studies [4,16,17], we could again demonstrate the presence of large amounts of CD34-positive cells and agar colonies after 7 days of culture in the presence of GM-CSF in active stages of AML and low amounts in remission. In previous experiments we could also demonstrate that the amounts of leukemic agar colonies are predictive of relapse [16].…”

Section: Clonogenic Assays Are An Appropriate Methods To Determine Andsupporting

confidence: 88%

“…CD34-positive agar colonies could also be detected in samples obtained from patients in remission of AML, but not in samples from healthy BM donors. As already shown, the persistence of clonogenic leukemic cells can also be proved at the clonal level by Southern blot analyses: clonal, gene-rearranged cells can be detected regularly in remission of AML [5,17,18]. Moreover, the differentiation capacity of cells can be estimated by evaluating the amounts of CD15-positive granulocyte agar colonies: proportions of CD15-positive cells or colonies were significantly higher in BM samples obtained from healthy BM donors or in remission of AML than in samples obtained at diagnosis or at relapse.…”

Section: Clonogenic Assays Are An Appropriate Methods To Determine Andmentioning

confidence: 99%

“…As already shown by others and ourselves, leukemic cells can differentiate -without losing their leukemic signs. That could mean that a 'preleukemic state', but no complete remission might be achieved by cytokine treatment in vitro [10,17,22]. In complete remission, a reduction in CD34-positive colonies was achieved in all examined cases.…”

Section: Cytokines Can Reduce But Not Eliminate Clonogenic Leukemic Cmentioning

confidence: 97%

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Influence of Cytokines and Autologous Lymphokine-Activated Killer Cells on Leukemic Bone Marrow Cells and Colonies in AML

Braun

Gerhartz²,

Schmetzer³

2001

Acta Haematol

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We have already shown that cytokine cocktails (IL-1ß, IL-3, IL-6, SCF, GM-CSF) and/or lymphokine-activated killer (LAK) cells can reduce the amounts of clonal, CD34-positive mononuclear bone marrow cells (BM-MNC) in acute myeloid leukemia (AML). In addition, the influence of those cocktails and/or LAK cells on the clonogenic potential of AML BM-MNC was investigated. BM colonies cultured in agar during different stages of the disease were immunophenotyped in situ: 17 patients at diagnosis, 14 patients in complete remission, 8 patients at relapse, 8 healthy donors. A significant reduction in leukemic cells and colonies positive for CD34 after in vitro culture of BM-MNC with cytokine cocktails was achieved with all samples obtained at diagnosis (n = 8, p ! 0.01), in 6 of 8 cases in complete remission but only in 2 of 6 cases at relapse. Cytokine cocktails stimulated granulopoiesis as well as B and T lymphopoiesis. Colonies with leukemic phenotype could never be detected in healthy BM. A significant reduction in leukemic colonies was achieved by coculture of BM-MNC (uncultured or cytokine precultured) with autologous LAK cells in all 4 cases at diagnosis and in 1 case at relapse. An additive effect of in vitro cytokine preincubation of BM samples on the leukemiareducing effect of LAK cells could be demonstrated in all samples studied (p ! 0.001; diagnosis: n = 10, relapse: n = 3, complete remission: n = 7). Patients had a better prognosis if CD34-positive colonies in AML could be reduced by cytokine incubation (p = 0.03) or coculture with autologous LAK cells in vitro (p = 0.04). Our data show that cytokines as well as LAK cells alone and in combination can reduce, however not eliminate clonogenic AML cells. Such mechanisms might be responsible for maintaining stable remissions in AML.

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Section: Clonogenic Assays Are An Appropriate Methods To Determine Andsupporting

confidence: 88%

Section: Clonogenic Assays Are An Appropriate Methods To Determine Andmentioning

confidence: 99%

Section: Cytokines Can Reduce But Not Eliminate Clonogenic Leukemic Cmentioning

confidence: 97%

See 1 more Smart Citation

Influence of Cytokines and Autologous Lymphokine-Activated Killer Cells on Leukemic Bone Marrow Cells and Colonies in AML

Braun

Gerhartz²,

Schmetzer³

2001

Acta Haematol

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“…UPA-R is involved in signal transduction of cytoplasmatic signals to the cytoskeleton. Therefore, some authors believe that UPA-R expression could play a role in adhesion, migration, and metastasis of leukemic cells [15][16][17] are characterized by high rates of extramedullar disseminations [18] that could, at least in part, be mediated by high expression of the UPA-R [15]. In leukemic patients, over-expression of the UPA-R is associated with increased consumption of plasma inhibitors, leading to increased bleeding complications [1].…”

Section: Upa-r Mediates Adhesion and Migration Of Tumor Cells And Hasmentioning

confidence: 99%

High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis

Graf¹,

Reif²,

Hecht³

et al. 2005

Am. J. Hematol.

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Urokinase-type plasminogen activator receptor (UPA-R; CD87) is a membrane protein responsible for plasmin expression on cells facilitating cellular extravasations and tissue invasions. We studied the expression of the UPA-R on bone marrow (BM) cells of 93 patients with acute myeloid leukemia at first diagnosis and 8 healthy probands as controls by FACS analysis using phycoerythrin (PE)-conjugated antibodies. A case was defined as UPA-R-positive (UPA-R + ) if >20% of the gated cells expressed UPA-R. Whereas none of the 8 healthy BM samples was positive for the UPA-R, 32 (34%) of the 93 AML samples were UPA-R + . Expression of UPA-R was heterogeneous in different FAB types, however, with the highest expression rates in monocytic subtypes (FAB M4/M5): 18%/19%/30% of UPA-R + cases were found in M1/M2 or M3, and 58%/80% of cases with M4 or M5 were UPA-R + .Proportions of UPA-R + cells varied between 1% and 98% of the mononuclear cell fractions, with the highest proportions in M4/M5 subtypes (on average 27%/40% UPA-R + cells) and the lowest expression in AML M2 (11% UPA-R + cells). The density of expressed UPA-R, estimated as mean channel fluorescence activity, was highest in cases with AML M1 (mFI: 124) followed by M4 and M5 (mFI: 78/77) and lowest in AML M2 (mFI: 43). In sAML, higher proportions of UPA-R + cases (8 of 18; 44%) compared to pAML (24 of 75; 32%) were found as well as higher proportions of UPA-R + cells (27% vs. 19%). Separating our patients' cohort in cytogenetic risk groups, we could not detect significant differences in the UPA-R expression profiles. For evaluations of the clinical course of AML, only patients treated by the AML-CG protocol (n = 65) were included. In the group of patients who did not respond to AML-CG therapy, significantly higher proportions of UPA-R + cells (31% vs. 14%, P = 0.0015, t-test) were found. By evaluating a cut-off value for the percentage of positive cells that allows the most significant separation and differentiation between cases with shorter or longer relapse-free survival times, we could show that patients with >26.5% UPA-Rpositive cells were characterized by a significantly higher risk for relapse compared to cases with <26.5% positive cells (P = 0.05). In summary, our data show a high expression of the UPA-R in AML, especially in (myelo)monocytoid subtypes. Cases with higher proportions of UPA-R + cells were characterized by a significant lower remission rate after AML-CG therapy and a higher risk for relapse. Although prospective trials are still lacking, UPA-R is a prognostically relevant factor independent from the karyotype. UPA-R positivity may identify subtypes of AML associated with a more aggressive clinical course. Thus due to lower remission probabilities in UPA-R + cases, a more intensive induction therapy regimen could be considered. Am.

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“…The main functions of MAC-1 are summarized in Table I. Extramedullary manifestations of leukemic cells often cause complications, especially in (myelo)-monocytoid subtypes of AML [3,4]. Such tissue infiltrations might be enabled by adhesion molecules like MAC-1.…”

Section: Introductionmentioning

confidence: 99%

Expression of MAC‐1 (CD11b) in acute myeloid leukemia (AML) is associated with an unfavorable prognosis

Graf¹,

Reif²,

Kröll³

et al. 2006

American J Hematol

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There is evidence to suggest, that cellular adhesion molecules and receptors could play a role in leukemia, e.g., through altered adhesive qualities of leukemic blasts. We have studied the expression of the b 2 -integrin Mac-1 (CD11b) on mononuclear cells in 48 patients with AML at first diagnosis by flow cytometry using a direct fluorescein-conjugated antibody. A case was defined as positive if more than 20% of the cells expressed Mac-1. Within the FAB types, we observed a high expression rate in cases with M5 (100% MAC-1 + cases, 73% MAC-1 + cells), M4 (75% MAC-1 + cases, 48% MAC-1 + cells) and in cases with FAB-M1 with 71% MAC-1 + cases and 29% MAC-1 + cells. Separating our patients' cohort in cytogenetic risk groups, we could detect significant higher proportions of MAC-1 + , cases (88% vs. 27%, P ¼ 0.005) and cells (51% vs. 16%, P ¼ 0.015) with poor cytogenetic risk compared to the favorable risk group. For clinical evaluations only patients treated according to the protocols of the German AML Cooperative Group (AML-CG) were included (n ¼ 29, cases with AML-M3 were excluded). More MAC-1 + cases and cells were found in the ''non-responders'' group (n ¼ 8) compared to the ''responders'' group (n ¼ 24). We can conclude that AML cases with high MAC-1 expression are characterized by a worse prognosis. Evaluation of MAC-1 expression in AML might therefore contribute clinically important data with respect to develop new therapies that influence the interactions between integrins like MAC-1 on leukemic cells and endothelial or immunoreactive cells. Am. J. Hematol. 81:227-235, 2006.

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Detection of Acute Myeloid Leukemic Cells in Complete Remission and in Extramedullary Sites by Clonal Analyses

Cited by 9 publications

References 5 publications

Influence of Cytokines and Autologous Lymphokine-Activated Killer Cells on Leukemic Bone Marrow Cells and Colonies in AML

Influence of Cytokines and Autologous Lymphokine-Activated Killer Cells on Leukemic Bone Marrow Cells and Colonies in AML

High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis

Expression of MAC‐1 (CD11b) in acute myeloid leukemia (AML) is associated with an unfavorable prognosis

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