肝硬化患者血浆GMP-140及vWF变化的初步探讨

目的探讨血浆血小板α－颗粒膜蛋白（ＧＭＰ－１４０）及血管性假血友病因子（ｖＷＦ）在肝硬化患者血中变化的临床及病理生理意义。方法采用双抗体夹心固相酶免疫试验方法分别定量测定４０例肝硬化患者与３１例对照者血浆ＧＭＰ－１４０及ｖＷＦ水平。结果发现肝硬化患者血浆ＧＭＰ－１４０、ｖＷＦ水平比对照组有非常显著的增高（Ｐ＜００１）,且发现肝硬化患者ＣｈｉｌｄＢ、Ｃ级均较ＣｈｉｌｄＡ级的ＧＭＰ－１４０水平显著升高（Ｐ＜００１）,有上消化道出血组比无出血组的血浆ＧＭＰ－１４０、ｖＷＦ水平亦明显增高（Ｐ＜００５）,同时还发现肝硬化组血浆ＧＭＰ－１４０、ｖＷＦ水平与血小板计数之间的关系均不相关（ｒ分别为－００３４９及－０１６２１,Ｐ＞００５）。结论肝硬化患者血浆ＧＭＰ－１４０、ｖＷＦ的升高可作为体内血小板活化与肝脏血管内皮细胞损伤的指标,可用来反映肝损伤状况及上消化道出血倾向。     

原发性高血压伴脑腔隙性病变患者凝血和纤溶系统失衡的研究

目的进一步探讨高血压病患者合并脑腔隙性病变者与凝血纤溶系统之间的关系,为早期防治寻找依据。方法健康对照组３１例及观察组轻中度高血压病患者５８例（根据头颅核磁共振分为脑腔隙性病变组（ｎ＝４６）和非脑腔隙性病变组（ｎ＝１２）进行组织型纤溶酶原激活物（ｔ－ＰＡ）及其抑制物（ＰＡＩ）的活性、血管性假血友病因子抗原（ｖＷＦ：Ａｇ）和纤溶酶原（ＰＩＧ）活性、凝血因子Ⅷ促凝活性（Ⅷ：Ｃ）测定。结果（１）高血压病组与对照组各项指标比较：前组ｔ－ＰＡ、ＰＡＩ、ＰＬＧ明显高于后组（Ｐ＜０．０１）,两组ｖＷＦ：Ａｇ、Ⅷ：Ｃ无明显差别;（２）腔隙性病变组与对照组比较：ｔ－ＰＡ（Ｐ＜０．０１）,ｖＷＦ：Ａｇ（Ｐ＜０．０５）明显高于对照组,Ⅷ：ｃ无明显变化;（３）非腔隙性病变组与对照组比较：前组ｔ－ＰＡ（Ｐ＜０．０５）,ＰＡＩ（Ｐ＜０．０１）明显高于后组,两组ＰＬＧ、ｖＷＦ：Ａｇ无明显变化;（４）脑腔隙性病变组与非腔隙性病变组比较：各项指标均无明显差异。结论高血压病无论是否合并腔隙性病变均存在凝血和纤溶功能的失衡,提示早期预防具有重要意义     

老年糖尿病患者止凝血变化的研究

目的 探讨老年糖尿病患者止、凝血变化及其临床意义。方法 分别检测老年糖尿病组和对照组止、凝血指标,包括血浆凝血酶－抗凝血酶Ⅲ复合物（ＴＡＴ）、血管性血友病因子抗原（ｖＷＦ：Ａｇ）、蛋白Ｃ抗原（ＰＣ：Ａｇ）、蛋白Ｓ抗原（ＰＳ：Ａｇ）、Ｐ－选择素（Ｐ－ｓｅｌｅｃｔｉｎ）、组织纤溶酶原激活物活性（ｔＰＡ：Ａ）、纤溶酶原激活剂抑制剂（ＰＡＩ－１：Ａ）及－二聚体（Ｄ－Ｄ）。结果 与对照组相比,老年糖尿病组的ＰＣ：Ａｇ、ＰＳ：Ａｇ和Ｄ－Ｄ均显著增高（Ｐ〈０．０５）,ｖＷＦ：Ａｇ、ＴＡＴ、ｔ－ＰＡ：Ａ、ＰＡＩ：Ａ、Ｐ－ｓｅｌｅｃｔｉｎ增高更为明显（Ｐ〈０．０１）。结论 老年糖尿病患者止、凝血功能异常主要表现为血管内皮损伤、凝血系统激活、纤溶活性降低和血小板的激活,这些止凝血的变化与糖尿病的血管并发症密切相关。     

高血压病内皮依赖性血管舒张及分泌功能的变化

目的：探讨内皮依赖性血管舒张功能和血浆内皮素、血管性假血友病因子、纤溶酶原激活物抑制物浓度在轻、中度高血压病中的变化及其相互关系。方法：采用高分辨率超声技术,对２１例轻、中度高血压病患者与２１名正常对照者的内皮依赖性血管舒张功能进行检测,同时测定血浆ＥＴ－１、ｖＷＦ、ＰＡＩ水平。结果：高血压病组反应性充血性肱动脉舒张率较对照组明显减弱（Ｐ〈０．００１）,而二组对硝酸甘油的反应无显著性差异（Ｐ〉０．０５）。在高血压病组血浆ｖＷＦ和ＥＴ－１水平明显高于正常对照组（Ｐ〈０．０５）。而二组间ＰＡＩ活性无显著性差异。结论：高血压病患者存在内皮依赖性血管舒张功能障碍,并有血浆ＥＴ－１、ｖＷＦ水平升高,将高分辨率Ｂ超技术检测内皮依赖性血管舒张功能和血浆ＥＴ－１、ｖＷＦ、ＡＰＩ水平结合起来分析可能有利于对高血压病患者病情的判断     

慢性特发性血小板减少性紫癜患者血小板功能有纤溶活性的观察

观察４３例慢性特发性血小板减少性紫癜患者血浆ｖＷＦ：Ａｇ，ＧＭＰ－１４０，ｔ－ＰＡ，Ａ，ＰＡＩ：Ａ及ＰＡｇＴ的改变，结果血浆ＧＭＰ－１４０及ｖＷＦ：Ａｇ明显高于对照组，提示慢性ＩＴＰ时存在血小板活化及血小板与人皮细胞粘附功能增强；ＰＡｇＴ低于正常组，表现血小板聚集性下降。纤溶活性指标：ｔ－ＰＡ：Ａ降低，ＰＡＩ：Ａ升高且呈正相关，表明慢性ＩＴＰ时有纤溶活性下降。     

纤溶系统缺陷在运动诱发心绞痛中的临床意义及机理探讨

本研究对经冠状动脉（冠脉）造影确定冠脉狭窄≥５０％的冠心病（ＣＨＤ）患者１８例，对照组１１例，采用平板运动试验诱发心绞痛（ＡＰ），同步检测运动前后血浆组织型纤溶酶原激活剂（ｔＰＡ）及其抑制物（ＰＡＩ）、纤维蛋白原（Ｆｇ）、血栓素Ｂ２（ＴＸＢ２）、６－酮类固醇－前列腺素Ｆ１０（６－ｋｅｔｏＰＧＦ１０）、肾素活性（ＰＲＡ）及血管紧张素Ⅱ（ＡｎｇⅡ）的变化，并根据平板运动试验结果将ＣＨＤ患者分为ＡＰ、非ＡＰ及阴性三组（各６例）进行比较。结果表明：ＡＰ组运动前后血浆Ｆｇ、ＰＡＩ活性、ＴＸＢ２、ＡｎｇⅡ水平均显著高于非ＡＰ组、阴性组及对照组，并且运动后的血浆ＴＸＢ２、ＡｎｇⅡ水平增加更显著；而运动前后的血浆ｔ－ＰＡ含量及活性水平却结果相反。揭示，基础水平血浆ｔ－ＰＡ活性低、ＰＡＩ活性高的ＣＨＤ患者，其血浆ＴＸＢ２、ＡｎｇⅡ水平亦高，ｔ－ＰＡ的促血小板解聚作用减弱，剧烈运动易进一步强烈激活血小板及肾素－血管紧张素系统诱发ＡＰ发作。     

急性白血病患者血浆可溶性Fas受体的水平及其意义

目的：了解急性白血病患者血浆可溶性Ｆａｓ（ｓＦａｓ）受体水平及其意义。方法：用酶联免疫吸附试验法（ＥＬＩＳＡ）检测３０例急性白血病患者的血浆ｓＦａｓ含量,并与正常对照组比较。结果：难治复发患者ｓＦａｓ含量（ＡＮＬＬ９．６９±３．５１μｇ／Ｌ; ｎ＝８,ＡＬＬ７．１４±２．１８μｇ／Ｌ; ｎ＝７）显著高于（ Ｐ＜０．０１）正常对照（３．４９±２．３６μｇ／Ｌ）和ＣＲ组（ＡＮＬＬ４．２３±１． ９８μｇ／Ｌ;ｎ＝８,ＡＬＬ ３．７２±０．７２μｇ／Ｌ; ｎ＝７）。 ＡＮＬＬ与 ＡＬＬ患者 ｓＦａｓ水平比较,差异无显著性（ Ｐ ＞０． ０５）。结论：初步提示血浆ｓＦａｓ水平升高与急性白血病预后不良有关。     

纤维蛋白原对内皮细胞t-PA和PAI-1 mRNA表达的影响

目的 探讨纤维蛋白原（Ｆｇ）对内皮细胞（ＥＣ）组织型纤溶酶原激活物（ｔ－ＰＡ）和纤溶酶原灭活剂（ＰＡＩ－１） ｍＲＮＡ表达的影响。方法 不同浓度Ｆｇ与ＥＣ孵育不同时间后,用单管逆转录聚合酶链反应（ＲＴ－ＰＣＲ）半定量法检测ｔ－ＰＡ和ＰＡＩ－ｍＲＮＡ的表达。结果 用２０,２００,２０００ｍｇ／Ｌ Ｆｇ与ＥＣ孵育１、１２、２４ｈ、ＰＡＩ－１ ｍＲＮＡ的相对表达水平分别为同时相对照组的１．７,３．６,２     

不稳定性心绞痛患者血浆vWF、GMP-140检测的临床意义

目的：探讨内皮及血小板活化功能在不稳定性心绞痛中的作用。方法采用ＥＬＩＳＡ双抗体夹心法测定不稳定性心绞痛１７例、稳定性心绞痛２５例,正常人２２例血浆ｖＷＦ（ｖｏｎＷｉｌｌｅｂｒａｎｄ因子,血管性假血友病因子）、ＧＭＰ－１４０（α颗粒膜蛋白－１４０）水平。结果不稳定性心绞痛组急必阶段血浆ｖＷＦ、ＧＭＰ－１４０显著高于稳定性心绞痛组和正常人组（Ｐ〈０．０１）,后两者之间无显著差异。不稳定性心绞痛组病情     

血浆α2纤溶酶抑制物和蛋白C活性与NIDDM血管病变的关系

测定５０例ＮＩＤＤＭ患者血浆α２纤溶酶抑制物（α２ＰＩ）和蛋白Ｃ（ＰＣ）活性，同时测定结合组织型纤溶酶原激活剂（ｔＰＡ）抗原和活性、ＰＡＩ活性及ｖｏｎＷｉｌｌｅｒｂｒａｎｄ因子（ｖＷＦ）含量。ＮＩＤＤＭ患者与正常对照组比较，除ｔＰＡ活性降低外，其余各项指标均增高。伴与不伴血管病变者比较，前者α２ＰＩ、ＰＣ、ＰＡＩ活性及ｖＷＦ含量均高于后者，ｔＰＡ活性低于后者，ｔＰＡ抗原无明显差异，α２ＰＩ、ＰＡＩ活性与ｔＰＡ活性呈负相关，ＰＣ活性与ｔＰＡ抗原和ｖＷＦ含量呈正相关。提示ＮＩＤＤＭ患者血浆中上述指标异常与血管病变的发生和发展有关。     

Circulating endothelial cells, endothelial precursors, VEGF and bFGF concentrations in patients with acute leukemias, lymphomas and myelomas

Circulating endothelial cells and their precursors are suggested by some authors to be novel markers of angiogenesis. The aim of the study was to measure circulating endothelial cells (CEC), circulating endothelial precursors (CEP) and activated endothelial cells (aCEC) and serum concentrations of VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor), well-known proangiogenic factors in patients with haematological malignancies before and after chemotherapy. Measurements were carried out in 20 patients with acute leukemia, 21 with malignant lymphoma and with 20 with multiple myeloma. The number of CEC, CEP and aCEC was measured by means of 3-color flow cytometry and serum concentrations of VEGF and bFGF with ELISA. In patients with acute leukemias and lymphomas the number of CEC was significantly higher than in controls, and that high number correlated with worse prognosis in patients with lymphomas. The increased number of CEP at diagnosis in patients with acute leukemia and lymphoma correlated with worse prognosis. The number of aCEC was higher in leukemic and lymphoma groups. After chemotherapy the decrease in CEC and CEP numbers in patients with acute leukemia and lymphoma was observed. In patients with lymphoma the increased serum VEGF concentrations in comparison with healthy subjects were noted but in leukemic patients-lower concentrations of VEGF. The initial high concentrations of bFGF in all patients did not change after therapy and in patients with lymphoma correlated with worse prognosis. Results suggest that in patients with acute leukemias and lymphomas CEC and CEP may be the markers of malignant process correlating with clinical outcome. aCEC may have a similar role in both diseases. Also in patients with lymphoma VEGF may be a marker of disease activity. bFGF is connected with pathogenesis of acute leukemia, myeloma and lymphoma and in patients with lymphoma is a predictor of worse prognosis.     

Vascular Endothelial Growth Factor Levels in Childhood Acute Lymphoblastic and Myeloblastic Leukemia

Angiogenesis has been associated with the growth, dissemination and metastasis and has been shown to be a prognostic. Although there are some data suggesting that angiogenesis may have a role in the pathophysiology of leukemia, its role in patient prognosis is yet to be defined. We analyzed the expression level of vascular endothelial growth factor (VEGF), an angiogenesis promoter and its possible- prognostic value in bone marrow samples at the time of diagnosis and remission of acute childhood leukemia patients. Besides 46 patients diagnosed as ALL or AML, 16 children were also included as a control group in the study. Our data have demonstrated that VEGF levels of AML patients were found higher than the control group statistically (P = 0.022). However we could not find any significant difference between VEGF levels of diagnosis and remission in both AML and ALL groups by blastic VEGF expression (P > 0.05). In this study the higher levels of VEGF in AML patients is one of the main findings although we were not able to assess any role of VEGF in predicting prognosis in pediatric leukemia patients by evaluating blastic cell VEGF expression. These results have demonstrated that the relationship between angiogenesis or angiogenesis promoters and hematological malignancies is not clear and simple as different methods or different cells beside different angiogenesis promotors are involved to these studies. So that not only tumor cells and their cytokines but also surrounding cells and their cytokines must be taken into consideration with the standardized study methods in the further studies to obtain a promising treatment approach.     

Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure.

We examined the changes in plasma levels of soluble thrombomodulin in 66 cases of disseminated intravascular coagulation (DIC), to investigate the damage to vascular endothelial cells and its relationship to multiple organ failure. A significant elevation of plasma levels of soluble thrombomodulin was observed in most cases of DIC, especially in patients with sepsis. However, no such significant elevation was observed in patients with acute promyelocytic leukemia. Plasma levels of both soluble thrombomodulin and active plasminogen activator inhibitor were higher in the cases of DIC with multiple organ failure than in those without multiple organ failure. The levels of soluble thrombomodulin were decreased with the clinical improvement in most cases of DIC but were further increased or remained at high levels in patients who showed no improvement of DIC. It was suggested that an increase in soluble thrombomodulin indicates the damage to the vascular endothelial cells in cases of DIC and that the damage to vascular endothelial cells plays some role in further progression of multiple organ failure.     

急性白血病患者细胞凋亡及血浆可溶性Fas/FasL测定的临床价值

为探讨凋亡相关基因、凋亡相关基因配体 (Fas/ Fas L )系统在白血病细胞逃避机体免疫监视方面的作用 ,采用酶联免疫吸附法 (EL ISA)测定了急性白血病患者白血病细胞的凋亡指数及其血浆中可溶性 Fas/ Fas L(s Fas/ s Fas L)水平。结果显示 ,急性非淋巴细胞白血病 (ANL L)、急性淋巴细胞白血病 (AL L)患者细胞凋亡指数明显低于对照组 (P均 <0 .0 1) ,其血浆 s Fas/ s Fas L 水平明显高于对照组 (P均 <0 .0 1) ;白血病细胞凋亡与血浆s Fas/ s Fas L 水平呈负相关 ,提示在白血病发病过程中 ,不但存在白血病细胞凋亡减少 ,而且存在 s Fas等抗凋亡因素增加 ,说明 Fas/ Fas L系统在白血病细胞逃避机体免疫监视方面起重要作用     

Physical contact with endothelial cells through β1- and β2- integrins rescues chronic lymphocytic leukemia cells from spontaneous and drug-induced apoptosis and induces a peculiar gene expression profile in leukemic cells

Background

Chronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia.

Design and Methods

We evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray-based gene expression profiles between leukemic cells at baseline and after co-culture.

Results

We found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both β₁- and β₂- integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFβ and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of anti-apoptotic molecules such as Bcl2 and Survivin.

Conclusions

Our study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells.     

Infection of human endothelial cells by human T-cell leukemia virus type I.

The effects of the human T-cell leukemia virus type I (HTLV-I) on cultured human endothelial cells were evaluated. Coculture of endothelial monolayers with either irradiated HTLV-producing lymphocytes or cell-free virus resulted in the production of multinucleated syncytia. The development of syncytia was inhibited by sera from patients with adult T-cell leukemia/lymphoma (ATLL). HTLV antigens were present on endothelial syncytia passaged in culture for greater than 3 months as detected by an anti-p19 monoclonal antibody, which detects a core protein of HTLV-I, and by ATLL sera. Moreover, these HTLV-infected endothelial cells were then able to infect and transform normal cord blood T lymphocytes with HTLV. These studies demonstrate that human endothelial cells are susceptible to productive HTLV-I infection in vitro and may have relevance for the spectrum of human disease associated with this family of retroviruses.     

Elevated levels of free tissue factor pathway inhibitor antigen in cases of disseminated intravascular coagulation caused by various underlying diseases.

Tissue factor pathway inhibitor (TFPI) is primarily synthesized by vascular endothelial cells and is found in vivo in association with endothelial cells, lipoproteins, or in free form. Free TFPI is the most potent and important type, because it is released from endothelial cells following an injection of heparin, or as a result of pathological stimuli. In order to study the role of TFPI in disease, the concentration of free form TFPI was measured in the plasma of 114 patients suffering from disseminated intravascular coagulation (DIC), as the result of several underlying diseases. Plasma antigen levels of free TFPI were significantly higher even in those patients not exhibiting DIC than in normal healthy subjects. These levels were even higher among patients exhibiting DIC, especially those with acute promyelocytic leukemia or cancer, receiving continuous heparin drip infusions. A significant correlation was observed between the plasma antigen levels of free form TFPI and those of fibrin/fibrinogen degradation products, and free form TFPI and plasmin inhibitor complex (r = 0.428, P < 0.0001 and r = 0.329, P < 0.0001, respectively) among 114 DIC patients. There were no significant differences between the plasma levels of free TFPI in DIC patients with or without multiple organ failure. It has been suggested that the plasma levels of free TFPI are closely related to the levels of fibrinolysis occurring in DIC patients, although further study is required to clarify the degree to which TFPI is expressed by endothelial cells during DIC.     

Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia

Shp2 tyrosine phosphatase plays a critical role in hematopoiesis, and dominant active mutations have been detected in the human gene PTPN11, encoding Shp2, in child leukemia patients. We report here that although no such mutations were detected in 44 adult leukemia patients screened, Shp2 expression levels were significantly elevated in primary leukemia cells and leukemia cell lines, as compared with normal hematopoietic progenitor cells. The Shp2 protein amounts correlated well with the hyperproliferative capacity but were inversely associated with the differentiation degree of leukemia cells. Suppression of Shp2 expression induced apoptosis and inhibition of leukemic cell clonogenic growth. Notably, the majority of Shp2 was preferentially localized to the plasma membrane and was constitutively phosphorylated on tyrosine in leukemia cells, and also in normal hematopoietic cells following mitogenic stimulation. Based on these results, we propose that aberrantly increased expression of Shp2 may contribute, collaboratively with other factors, to leukemogenesis.     

Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis

Arsenic trioxide (As(2)O(3)) has recently been used successfully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro. However, the mechanism by which As(2)O(3) exerts its antileukemic effect remains uncertain. Emerging data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that activated endothelial cells release cytokines that may stimulate leukemic cell growth. Leukemic cells, in turn, can release endothelial growth factors, such as vascular endothelial growth factor (VEGF). On the basis of these observations, we hypothesized that As(2)O(3) may interrupt a reciprocal loop between leukemic cells and the endothelium by direct action on both cell types. We have shown that treatment of proliferating layers of human umbilical vein endothelial cells (HUVECs) with a variety of concentrations of As(2)O(3) results in a reproducible dose- and time-dependent sequence of events marked by change to an activated morphology, up-regulation of endothelial cell adhesion markers, and apoptosis. Also, treatment with As(2)O(3) caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVECs with As(2)O(3) prevented capillary tubule and branch formation in an in vitro endothelial cell-differentiation assay. In conclusion, we believe that As(2)O(3 )interrupts a reciprocal stimulatory loop between leukemic cells and endothelial cells by causing apoptosis of both cell types and by inhibiting leukemic cell VEGF production. (Blood. 2000;96:1525-1530)     

Leukemia-stimulated bone marrow endothelium promotes leukemia cell survival

Extensive endothelial cell proliferation and marked neovascularization are the most pronounced microenvironmental changes consistently observed in the bone marrow (BM) of patients with acute lymphoblastic leukemia (ALL). It is not known whether ALL cells induce this phenotype and whether they receive critical signals from the tumor-associated BM endothelium. Here, we show that leukemia cells actively stimulate BM endothelium, promote de novo angiogenesis, and induce neovascularization in the leukemic BM. Soluble factors, present in the leukemic BM microenvironment, promote the proliferation, migration, and morphogenesis of BM endothelial cells, which are critical processes in tumor angiogenesis. We also show in vitro that leukemia cells display directional motion towards assembled BM endothelium and following adherence exhibit cell polarization, pseudopodia, and ultrastructural features that suggest the existence of leukemia-endothelium cross-talk. Finally, we show that BM endothelium promotes leukemia cell survival through a mechanism mediated through the anti-apoptotic molecule bcl-2. These studies indicate that ALL cells actively recruit BM endothelium and mediate the leukemia-associated neovascularization observed in ALL. Therefore, disruption of interactions between leukemia cells and BM endothelium may constitute a valid therapeutic strategy.