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

Abstract

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.

Clinical Significance of CD87 Expression in Acute Myeloblastic Leukemia.

“…It was emphasized that its expression was more prominent in leukemias with monocytoid differentiation and associated with poor prognosis. 7 Some other studies have also reported similar results. 13 We could not detect any relationship between CD87 and CR since, in our opinion, the number of monocytoid AML cases was low for an accurate statistical analysis.…”

“…It may also explain the relationship between CD87 and the frequency of organomegaly. 1,7 A significant relationship between CD87 and organomegaly was also found (p< 0.05).…”

“…Since co-expression of CD87 and CD34 does not present on normal hematopoietic cells, the presence of such a combination may be used for the detection of leukemic cells in patients in remission, during the follow-up period of residual disease. 5,7 Graf et al showed the relationship between CR and CD87 and reported a lower remission rate and a shorter disease-free survival in patients with AML expressing CD87 at a high degree. It was emphasized that its expression was more prominent in leukemias with monocytoid differentiation and associated with poor prognosis.…”

“…1,5 Their functions in healthy cells include the conversion of plasminogen into plasmin, the extravasation associated with proteolytic breakdown of the adhesion molecules which are responsible from cell contact, the regulation of cytoskeletondependent events such as mobility and degranulation and increased bleeding tendency. [6][7][8][9][10] In clonal hematopoietic disorders, CD87 expression studies have focused on acute leukemias and multiple myeloma. We studied CD87 expression frequency with flow cytometry method in patients with AML.…”

Urokinase and its receptors in chronic kidney disease

“…The complex molecular interactions between uPAR and its ligands or co-receptors regulate key events during cell adhesion, migration, proliferation and survival. The most extensive studies performed to date pertain to its role in tumor invasion and metastasis (37)(38)(39)(40).…”