High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis
High expression of urokinase plasminogen activator receptor (UPA-R) in acute myeloid leukemia (AML) is associated with worse prognosis
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DOI：
10.1002/ajh.20337
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发表时间：
2005-05-01
影响因子：
12.8
通讯作者：
Schmetzer, H
中科院分区：
文献类型：
--
作者：
Graf, M;Reif, S;Schmetzer, H
尿激酶型纤溶酶原激活物受体（UPA-R; CD 87）是一种负责纤溶酶在细胞上表达的膜蛋白，促进细胞外渗和组织侵袭。应用藻红蛋白（PE）标记的抗体，通过流式细胞仪（FACS）检测了93例初诊急性髓系白血病患者和8例健康先证者骨髓（BM）细胞UPA-R的表达。如果> 20%的门控细胞表达UPA-R，则将病例定义为UPA-R阳性（UPA-R+）。而8个健康骨髓样本中没有一个是UPA-R阳性的，93个AML样本中有32个（34%）是UPA-R+。UPA-R在不同类型FAB中的表达具有异质性，但在单核细胞亚型（FAB M4/M5）中表达率最高：18%/19%/30%的UPA-R+病例见于M1/M2或M3，58%/80%的M4或M5病例为UPA-R+。UPA-R+细胞的比例在单核细胞组分的1%和98%之间变化，其中M4/M5亚型中的比例最高（平均27%/40% UPA-R+细胞），AML M2中的表达最低（11% UPA-R+细胞）。表达的UPA-R的密度，估计为平均通道荧光活性，在AML Ml（mFl：124）的病例中最高，其次是M4和M5（mFl：78/77），并且在AML M2（mFl：43）中最低。在sAML中，发现UPA-R+病例的比例（18例中的8例; 44%）高于pAML（75例中的24例; 32%），以及UPA-R+细胞的比例更高（27% vs. 19%）。将我们的患者队列分为细胞遗传学风险组，我们不能检测到UPA-R表达谱的显著差异。对于AML临床病程的评价，仅纳入了接受AML-CG方案治疗的患者（n = 65）。在对AML-CG治疗无反应的患者组中，UPA-R+细胞的比例显著高于对照组。（31%对14%，P= 0.0015，t检验）。通过评估阳性细胞百分比的截止值，该截止值允许在具有较短或较长无复发存活时间的病例之间进行最显著的分离和区分，我们可以表明，与阳性细胞<26.5%的患者相比，UPA-R阳性细胞> 26.5%的患者复发风险显着更高（P= 0.05）。总之，我们的数据显示UPA-R在AML中的高表达，特别是在（髓）单核细胞样亚型中。UPA-R+细胞比例较高的病例在AML-CG治疗后的缓解率显著降低，复发风险较高。虽然前瞻性试验仍然缺乏，UPA-R是一个独立于核型的遗传学相关因素。UPA-R阳性可识别与更具侵袭性的临床病程相关的AML亚型。因此，由于UPA-R+病例的缓解概率较低，可以考虑更强化的诱导治疗方案。Am. J. Hematol. 79：26-35，2005. (c)2005 Wiley-Liss，Inc.
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 (mFl: 124) followed by M4 and M5 (mFl: 78/77) and lowest in AML M2 (mFl: 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-R-positive 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. J. Hematol. 79:26-35, 2005. (c) 2005 Wiley-Liss, Inc.