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Abstract: Central nervous system (CNS) relapse remains an important cause of morbidity and mortality in acute leukemia, but the mechanisms of CNS infiltration are poorly understood. Some results have shown the blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. The authors ask how can leukemic cells disrupt BBB and then successfully enter the CNS in the process of leukemia metastasis. Tight junctions between brain microvessel endothelial cells (BMECs) of BBB possess an intricate complex of transmembrane proteins with cytoplasmic accessory proteins, and hence act as physiological and pharmacological barrier, thereby preventing influx of molecules from the bloodstream into the brain. So the loss of endothelial tight-junction proteins might be an important event related to the disruption of BBB. Vascular endothelial growth factor (VEGF) is one of the potent mediators of vascular permeability and the VEGF secreted by leukemic cells may be implicated in this response. Leukemic cells not only produce VEGF, but also express functional VEGFR, resulting in an autocrine loop for tumor growth and dissemination. It has been observed that forced VEGF over expression triggers proliferation and migration/invasion of some leukemic cells, thereby inducing a more invasive tumor phenotype. It has been identified that VEGF-mediated disruption of endothelial transmembrane tight-junction proteins is contributed to the breakdown of BBB in some CNS inflammation disease. Here, we hypothesize that VEGF secreted by leukemic cells also plays an important role in increasing the permeability of BBB by disrupting endothelial tight-junction proteins and give leukemic cells an entrance to the CNS in CNS leukemia. We propose the key tight-junction proteins claudin-5, occludin, and ZO-1 as targets of VEGF action in promoting BBB breakdown, and in interfering with the VEGF/VEGFR pathway using anti-VEGF or anti-VEGFR antibodies can reduce the permeability of BBB. All these will be tested on the BBB model in vitro and in vivo based on an animal model of CNS leukemia. This hypothesis is useful for exploring the mechanism of leukemic CNS infiltration. If correct, the mechanism put forward here will provide a potent evidence for anti-VEGF strategies in treatment of CNS leukemia. [Copyright &y& Elsevier]

Abstract: The frequency of extramedullary infiltration (EMI) in acute myeloblastic leukemia (AML) is reported up to 40% and most prevalent in myelo-monoblastic and monoblastic subtypes of AML (M4 and M5 according to FAB classification). The majority of patients with EMI suffered poor prognosis. To explore mechanism underlying EMI, we analyzed SHI-1 cells, a highly invasive human acute monocytic leukemia cell line, and found their strong expression of matrix metalloproteinase 2 (MMP-2), membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase 2 (TIMP-2). SHI-1 cells showed higher invasive ability to traverse reconstituted basement membranes (Matrigel) and stronger activation of proMMP-2 than other leukemia cell line such as NB4, K562, U937 and THP-1 cells. When co-cultured with bone marrow stromal cells (BMSCs), the invasive capacity and proMMP-2 activation of SHI-1 cells enhanced remarkably. Furthermore, the inhibition of MMP-2, MT1-MMP, or TIMP-2 by small interfering RNA (siRNA) substantially impaired SHI-1 cells invasion and decreased proMMP-2 activation. In the contrast, up-regulated expression of TIMP-2 for 2–3 folds level increased cell invasion and proMMP-2 activation. These results demonstrated that constitutively high expression of MMP-2, MT1-MMP and TIMP-2 in SHI-1 cells facilitated cell invasion by promoting proMMP-2 activation. Moreover, up-regulation of TIMP-2 exhibited not a repressive but an activating effect on SHI-1 cells invasion. Our study indicated that increasing TIMP-2 in AML patients with EMI may potentially cause adverse effects, particularly in patients containing high levels of MMP-2 and MT1-MMP. [Copyright &y& Elsevier]

Abstract: TNFR-associated factors (TRAFs) participate in diverse biological processes, such as adaptive and innate immunity, stress response, and bone metabolism. We report that all TRAFs except TRAF3 are expressed at mRNA and protein levels in B cell-derived Hodgkin''s lymphoma cell lines (L428 and KM-H2). Both the classical (p50–RelA) and the alternative NF-κB activity (p52–RelB) are sustained in L428 and KM-H2 cells. A successful depletion of TRAF1 protein expression by means of RNA interference abrogates the anti-apoptosis activity in L428 cells. The TRAF1-deficiency reduces the classical NF-κB activity but not the alternative activity. The expression of the NF-κB targeting genes, such as ICAM-1, c-Flip, and Cyclin D1, is suppressed in the TRAF1-depleted cells. On the other hand, CD30 signaling upregulates the TRAF1 expression while reducing the expression of TRAF2 and TRAF5. Importantly, the CD30-induced alternative NF-κB activation is inhibited by the depletion of the TRAF1 expression. We also demonstrate that the phosphorylation of the extracellular signal-regulated kinase (ERK) upon CD30 stimulation in Hodgkin''s lymphoma cells is independent of TRAF1 expression. Our data shed new light on the function of TRAF1 in B cell-derived lymphoma cells. We conclude that TRAF1 is an important molecule mediating both the CD30 signaling-dependent and independent NF-κB activation, which prevents the lymphoma cells from spontaneous and induced apoptosis. [Copyright &y& Elsevier]